Questions or comments regarding the content of the NHPD Monthly Communiqué may be addressed to

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1 The NHPD Monthly Communiqué is a publication of Health Canada s Natural Health Products Directorate (NHPD), the federal department responsible for the regulation of natural health products sold in Canada. The communiqué is released to the Canadian public the first week of each month via the NHPD s electronic bulletin. Subscription to this e-bulletin is available at Questions or comments regarding the content of the NHPD Monthly Communiqué may be addressed to NHPD_DPSN@hc-sc.gc.ca. TABLE OF CONTENT: ******************************************************************** Each NHPD Monthly Communiqué is separated into five sections for ease of reference. These are: Product Licensing Information, Site Licensing Information, Compliance Corner, Clinical Trial Information and Other Information. PRODUCT LICENSING INFORMATION Final Classification of Medicinal Ingredients listed in the Category IV Monographs/TPD Labelling Standards P. 2 Determining Proper and Common Names for Homeopathic Medicines P. 2 Classification and Regulation of Gotukola P. 4 Correction to the Response time for PDNs and IRNs P. 4 Rationale for Combination Products P. 5 Clarification Regarding Vitamin A and Vitamin E Conversion Factors P. 5 o Vitamin A Conversion Table P. 5 o Examples Using Vitamin A Conversion Factors P. 6 o Vitamin E Conversion Tables P. 7 o Examples Using Vitamin E Conversion Factors P. 8 Common Errors and Deficiencies P. 8 SITE LICENSING INFORMATION P. 9 COMPLIANCE CORNER Site Licensing and Health Canada's compliance approach for natural health P. 9 products POST January 1, CLINICAL TRIAL INFORMATION P. 10 OTHER INFORMATION P. 10 Page 1 of 10

2 PRODUCT LICENSING INFORMATION: Final Classification of Medicinal Ingredients listed in the Category IV Monographs/TPD Labelling Standards For over a year, members of the Natural Health Products Directorate and Therapeutic Products Directorate have been working diligently on the classification of roughly 425 medicinal ingredients found in the Category IV Monographs/TPD Labelling Standards. We are pleased to announce that this exercise is now complete and all medicinal ingredients found in these monographs and labelling standards have been officially classified. The list of ingredients, which is available on-line at is organized by the name of the monograph or labelling standard and includes the ingredient name and its classification (i.e. as a natural health product or drug) In addition, we would also like to announce that the conversion of several Category IV Monographs/TPD Labelling Standards into official natural health product monographs is progressing well. Several new monographs have been drafted and are currently in the peer-review stage. It is anticipated that the complete conversion will be done by Spring 2006, at which time applicants citing these new monographs will see their applications processed within a 60-day timeframe. Determining Proper and Common Names for Homeopathic Medicines Part 4 of the Product Licence Application (PLA) Form asks that applicants provide the proper and common names for each medicinal ingredient found in their natural health product. The following guidelines apply specifically to applications for homeopathic medicines and are developed to assist applicants in differentiating between the proper name and common name for medicinal ingredients in homeopathic medicines. Please refer to this information when filling out the proper and common name fields on the Product Licence Application form. **Please note that the proper name is not necessarily the name listed at the top of the homeopathic monograph in a homeopathic pharmacopoeia. Proper Names 1. When the starting material for the medicinal ingredient is a plant or a plant material, an alga, a fungus, a bacterium, a nonhuman animal material or a probiotic, the proper name will be the current Latin name of its genus and, if any, its specific epithet. Example: Allium cepa. 2. When the ingredient is a mineral or chemical, the proper name will be any unambiguous name. Example: ferrous iodide. 3. When the ingredient is a vitamin, the proper name will be a name set out for that vitamin in Item 3 of Schedule 1 of the Natural Health Products Regulations. These are: biotin, folate, niacin, pantothenic acid, vitamin A, thiamine, riboflavin, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E and vitamins K1 and K2. 4. When the ingredient is a nosode, the proper name is the current scientific Latin binomial of the diseasecausing agent. Example: Bordetella pertussis. Page 2 of 10

3 5. When the ingredient is a sarcode, the proper name is the name of the tissue used. Example: Thyroid The following Internet links may be useful in identifying the proper name of a given medicinal ingredient for your homeopathic medicines: For plants and plant materials: For animals and animal materials: For chemicals: Common Names For homeopathic medicines, the common name of a medicinal ingredient is any name by which it is commonly known, provided it is a name listed in one of the accepted homeopathic pharmacopoeias. The following table provides a few examples: Proper Name Allium cepa Ferrous iodide Bordetella pertussis Thyroid Sodium chloride Acceptable Common Names onion, oignon ferrum iodatum, iodure de fer pertussinum, pertussin, coqueluchin thyroidinum, thyroid gland, thyroïde natrum muriaticum, salt, table salt, sea salt, sel marin, chlorure de sodium marin The NHPD recognizes that there may be cases where the proper name and common name will be identical. For example, the proper name for basil is Ocimum basilicum and the common name may be Ocimum basilicum or basil. If Ocimum basilicum is chosen as the common name, it is only necessary to list the name once (in the proper name field of the PLA form). In this case, the common name field may be left blank because the common name chosen is identical to the proper name. However, if basil is chosen as the common name it must be listed on the PLA form because it is different from the proper name (which, as indicated, is Ocimum basilicum). Page 3 of 10

4 Classification and regulation of gotukola Products containing gotukola crude herb or part(s) of the herb are now classified and regulated as natural health products. Individuals and businesses seeking authorization to market these products in Canada are first required to obtain the necessary product and site licenses. Products containing gotukola extract or active principles thereof will continue to be classified and regulated as prescription drugs. The Natural Health Products Regulations prohibit natural health products from containing a substance or a combination of substances currently listed on Schedule F of the Food and Drugs Regulations. Schedule F is a listing of substances which require a prescription in Canada. Since the coming into force of the Regulations in 2004, there have been ongoing discussions regarding the current inclusion of substances or combinations of substances on Schedule F of the Food and Drug Regulations which may otherwise be considered natural health products. Among these substances is Centella asiatica, commonly known as gotukola. In December 2005, following extensive discussions between departmental representatives and industry stakeholders, a decision was reached regarding the classification and regulation of this particular substance. The present listing of gotukola on Schedule F is set out as "Centella asiatica extract and active principles thereof." While from a scientific perspective, a product containing gotukola crude herb or part(s) of the herb consists of "Centella asiatica extract and active principles thereof", it was agreed that the Schedule F listing was intended to include extract products specifically, and not products which contain the crude herb or part(s) thereof. The decision was thus made that the current Schedule F listing applies to extracts and active principles only and does not apply to products consisting of the crude herb or parts thereof. Correction to the Response Time for PDNs and IRNs In the December 2005 issue of the Monthly Communiqué, we had indicated in our article entitled Intent to Withdraw Notice will no longer be sent after January 1, 2006 that applicants are required to respond to a Processing Deficiency Notice (PDN) or Information Request Notice (IRN) within 30 business days. However, we wish to inform you that this should have said 30 calendar days. We apologize for this oversight on our part. As of January 1st, 2006, applicants who do not respond within the time frame indicated in the PDN or IRN (30 calendar days) will receive a Notice of Withdrawal and their applications will be immediately removed from our review queue. Page 4 of 10

5 Rationale for Combination Products The NHPD allows for any combination of medicinal substances listed in Schedule 1 of the Natural Health Products Regulations provided that this combination contributes to the recommended use/purpose of the product and does not present any safety concerns. However, for combination products that contain medicinal ingredients that do not contribute directly or obviously to the recommended use/purpose indicated, an explanation, or rationale, for the addition of these medicinal ingredients to the product is required. Applicants who cannot provide a strong rationale supporting the inclusion of a medicinal ingredient in their combination will be asked to remove that ingredient from the formulation. Clarification Regarding Vitamin A and Vitamin E Conversion Factors Over the past months, we have received a number of questions regarding the vitamin A and vitamin E conversion factors that were published in the October and November 2005 issues of the NHPD Monthly Communiqué. As such, it is the intent herein to provide clarification and examples on how to use the conversion factors for each of these substances. VITAMIN A The following is an elaborated version of the table published in the October issue of the Monthly Communiqué and presents vitamin A conversion factors. Quantity of Source Material 1 µg all-trans-retinol (1 µg RAE) (synonym: vitamin A) 1 µg of all-trans-retinyl acetate (synonym: vitamin A acetate) 1 µg all-trans-retinyl palmitate (synonym: vitamin A palmitate) 1 µg supplemental all-trans-beta-carotene (synonym: beta-carotene) i.e. as an isolate 1 µg dietary all-trans-beta-carotene (synonym: beta-carotene) i.e. in plant (e.g. carrot powder), algal, or bacterial matrices 1 µg supplemental all-trans-alpha-carotene or all-trans-betacryptaxanthin (synonyms: alpha-carotene and beta-cryptaxanthin) i.e. as isolates 1 µg dietary all-trans-alpha-carotene or all-trans-beta-cryptaxanthin (synonyms: alpha-carotene and beta-cryptaxanthin) (e.g. in citrus fruit powder) Vitamin A Activity (in International Units) 3.33 IU 2.91 IU 1.82 IU 1.67 IU 0.28 IU 0.83 IU 0.14 IU 1 Retinol Activity Equivalent (1 µg RAE): = 1 µg all-trans-retinol = 2 µg supplemental all-trans-beta-carotene = 12 µg dietary all-trans-beta-carotene = 24 µg dietary all-trans-alpha-carotene or all-trans-beta-cryptaxanthin Page 5 of 10

6 Points of Clarification: In the PLA form, the quantity of vitamin A must always be provided in terms of retinol activity equivalents (RAE) (i.e. in µg of all-trans-retinol), irrespective of the source material used. International Units (IU) may be provided as optional additional information on the PLA form in the potency field and on product labels. The only acceptable claim for beta-carotene (for compendial applications) is as a source of vitamin A (e.g. beta-carotene as provitamin A ). In the PLA form vitamin A should be identified as the proper name, and vitamin A, retinol or betacarotene as provitamin A should be identified as the common name. 1 IU of vitamin A activity = 1 IU of beta-carotene activity because beta-carotene is acting as a source of vitamin A. Examples using the Vitamin A Conversion Factors: a) Converting IU of vitamin A activity into RAE Convert 500 IU of vitamin A activity from all-trans-retinol into RAE: (500 IU vitamin A) x (1 µg RAE) = 150 µg RAE 3.33 IU vitamin A b) Converting weight of vitamin A source material into RAE Convert 2000 µg of supplemental all-trans β-carotene (i.e. β-carotene dissolved in vegetable oil) into RAE. Step 1: Convert the source material into IU activity using the conversion table. NOTE - According to the conversion table, 1 µg of supplemental β-carotene is equal to 1.67 IU of vitamin A: (2000 µg of supplemental β-carotene) x (1.67 IU vitamin A) = 3340 IU vitamin A 1 µg supplemental β-carotene Step 2: convert IU activity into RAE: (3340 IU vitamin A) x (1 µg RAE) = 1000 µg RAE 3.33 IU vitamin A ANSWER: 2000 µg of supplemental all-trans β-carotene = 1000 µg RAE Convert 2000 µg of dietary all-trans β-carotene (i.e. in carrot powder) into RAE. Step 1: Convert the source material into IU activity using the conversion table. NOTE - According to the conversion table, 1 µg of dietary β-carotene is equal to 0.28 IU of vitamin A: (2000 µg of dietary β-carotene) x (0.28 IU vitamin A) = 560 IU Vitamin A 1 µg supplemental β-carotene Page 6 of 10

7 Step 2: Convert IU activity into RAE: (560 IU vitamin A) x (1 µg RAE) = 168 µg RAE 3.33 IU vitamin A ANSWER: 2000 µg of dietary all-trans β-carotene = 168 µg RAE In order to facilitate the application process and reduce the number of Information Request Notices (IRNs) sent out, the NHPD kindly asks that applicants provide their vitamin A calculations with their product licence submissions. VITAMIN E The following two tables present vitamin E conversion factors in a more simplistic format compared to the table published in the November issue of the Monthly Communiqué. The first table shows how to convert the weight of vitamin E source material into the quantity of vitamin E as alpha-(α)-tocopherol equivalents (ATE) (i.e. in mg of RRR-α-tocopherol) and the second table shows the factors for converting International Units (IU) of vitamin E into the quantity of vitamin E as ATE. Source Material Quantity of Vitamin E (ATE) International Units (IU) 1 mg RRR-α-tocopherol 1.00 mg mg RRR-α-tocopheryl acetate mg mg RRR-α-tocopheryl succinate mg mg all racemic(rac)-α-tocopherol mg mg all rac-α-tocopheryl acetate mg mg all rac-α-tocopheryl succinate mg Source Material Quantity of Vitamin E (ATE) 1 IU RRR-α-tocopherol 0.67 mg 1 IU RRR-α-tocopheryl acetate 0.67 mg 1 IU RRR-α-tocopheryl succinate 0.67 mg 1 IU all rac-α-tocopherol 0.45 mg 1 IU all rac-α-tocopheryl acetate 0.45 mg 1 IU all rac-α-tocopheryl succinate 0.45 mg Points of Clarification: In the PLA form, the quantity of vitamin E must always be provided in terms of ATE, irrespective of the source material used. IU may be provided as optional additional information in the PLA form in the potency field and on product labels. RRR-α-tocopherol is the only natural source of vitamin E. The other five forms are considered synthetic. RRR and all rac-α-tocopherol are more specific names for what were previously known as d and dl-αtocopherol, respectively. Page 7 of 10

8 Example using the Vitamin E Conversion Factors: a) Converting weight of vitamin E source material into ATE. Convert 200 mg of RRR-α-tocopheryl succinate into ATE: (200 mg RRR-α-tocopheryl succinate) x (0.807 mg ATE) = mg ATE 1 mg RRR-α-tocopheryl succinate Convert 200 mg all rac-α-tocopheryl acetate into ATE: (200 mg all rac-α-tocopheryl acetate) x (0.456 mg ATE) = 91.2 mg ATE 1 mg all rac-α-tocopheryl acetate b) Converting vitamin E activity in terms of IU into ATE. Convert 400 IU RRR-α-tocopheryl succinate into ATE: (400 IU RRR-α-tocopheryl succinate) x (0.67 mg ATE) = 268 mg ATE 1 IU RRR-α-tocopheryl succinate Convert 400 IU all rac-α-tocopherol into ATE: (400 IU all rac-α-tocopherol) x (0.45 mg ATE) = 180 mg ATE 1 IU all rac-α-tocopherol In order to facilitate the application process and reduce the number of Information Request Notices (IRNs) sent out, the NHPD asks that applicants provide their vitamin E calculations with their product licence submissions. Common Errors and Deficiencies The following is a list of common errors and deficiencies found in product licence applications sent to the NHPD. These errors, though they may seem minor in some cases, can lead to major time delays and can be easily avoided if applicants take the time to properly prepare and review their applications before submitting them to the NHPD. 1. Duration of Use information: Duration of use information should only appear in the Duration of Use field found in Part 4, Section 3 of the PLA form. It has been noted that duration of use information has erroneously appeared in the risk information fields (Cautions and Warnings, Contra-indications, Known Adverse Reactions) also found in Part 4, Section 3 of the PLA form. This error leads to unnecessary questions, additional clarifications and review delays. If the duration of use information is too long for the Duration of Use field, the applicant can put a star annotation in the field (*) and include the annotated duration of use text somewhere else on the same page of the PLA form, cross referencing it with the same symbol (e.g. *). ******************************************************************** Page 8 of 10

9 SITE LICENSING INFORMATION: This month s focus was to have been on storage and maintenance of facilities. However, with the site licensing provisions of the Regulations coming into force on January 1, 2006, all of our site licensing resources have been focussed wholly on processing site licence submissions. Next month will see the resumption of our educational theme-based series on site licensing, with part four focussing on storage and maintenance of facilities. COMPLIANCE CORNER: ******************************************************************** In addition to authorizing the sale of natural health products, the NHPD is also responsible for coordinating compliance efforts targeted at natural health products that are not in compliance with the Natural Health Product Regulations and related policies and/or that pose an unacceptable risk to the health and safety of Canadians. Site Licensing and Health Canada's compliance approach for natural health products POST January 1, In order to market natural health products in Canada, the Natural Health Products Regulations first require individuals and businesses to obtain the necessary product and site licences. Prior to January 1, 2006, Health Canada s compliance efforts had focussed on products, targeting those that A) present a significant risk to the health of the population or B) have not been issued a submission number prior to their product category priority date. However, on January 1, 2006, the site licensing provisions of the Regulations came into effect and compliance actions are now focussing on both products and sites. Individuals and businesses without a valid site licence will be subject to compliance action by the Health Products and Food Branch Inspectorate. For example, products for which a site license has not been obtained by the necessary individuals or businesses and that are referred to the Inspectorate by the Canadian Border Services Agency, will be recommended for refusal of entry into Canada. When products are encountered in Canada, for which a site license has not been obtained by the necessary individuals or businesses, the Inspectorate will take compliance and enforcement action in accordance with POL Having a valid product licence or submission number without a site license does not constitute authorization to sell nor does it exempt an individual or business from compliance action. The same applies to natural health products whose priority categorization has not yet passed (i.e. products found in priorities 4, 5, and 6). Priority 4, 5 and 6 products without a valid site licence will be subject to compliance action. Industry stakeholders that have not yet applied for either licence are encouraged to do so immediately. ******************************************************************** Page 9 of 10

10 CLINICAL TRIAL INFORMATION: No new information to report this month. However, keep an eye out for the second issue of the NHPD Quarterly Report (scheduled for release in late February 2006), which will include a progress report from the NHPD s Clinical Trials Unit describing some of its recent accomplishments, which include the elimination of the clinical trial application backlog. The NHPD Quarterly Report is available on-line at OTHER INORMATION: No new information to report this month. ******************************************************************** Page 10 of 10