1. Proposed Gluten Regulations in Argentina Excipient Realities and Global Requirements

2. Proposed Gluten Regulations Commercialized medicines will be required to have a tag that says "gluten free" and the corresponding symbol. These medicines will have to be analytically tested to demonstrate that the product is gluten free. The test methods used will have to be approved by INAME, and the manufacturer will have to present the test method they use, and request for INAME for their approval. The tests have to be performed on the finished product, intermediate product and raw materials. Also, the raw material suppliers will have to present a test method aligned with the corresponding specifications.

3. Proposed Gluten Regulations All the oral administered medicines registered in INAME will have to meet this regulation in a term of 12 months. If a medicine needs gluten as part of the formulation, it will have to be justified to INAME and quantified. If accepted by INAME, the medicine will be required to have a tag that says "this medicine has gluten". Reference: http://www.anmat.gov.ar/boletin_anmat/BO/Disposicion_ 2574-2013.PDF http://www.anmat.gov.ar/boletin_anmat/BO/Disposicion_ 2574-2013.PDF

4. Excipient Realities & Global Requirements Global Industry (makers and users of excipients) will not test all drugs and ingredients for gluten, especially when there is no reason to think that it is likely to be present This would be redundant testing and a waste of resources No other countries require testing of all drugs and ingredients for gluten Gluten free status is not currently a requirement anywhere

5. Excipient Realities & Global Requirements FDA and EU have proposed food regulations which would require that a food product would have to be <20 ppm gluten to be labeled as gluten free – http://www.ofr.gov/(X(1)S(rdn21uray1n5vjjgy2ldbyng))/OFRUpload/O FRData/2013-18813_PI.pdf http://www.ofr.gov/(X(1)S(rdn21uray1n5vjjgy2ldbyng))/OFRUpload/O FRData/2013-18813_PI.pdf – http://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:016:0003:0005 :EN:PDF http://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:016:0003:0005 :EN:PDF – http://www.food.gov.uk/multimedia/pdfs/glutenfaqs.pdf http://www.food.gov.uk/multimedia/pdfs/glutenfaqs.pdf However, routine testing is NOT required – See comment #22 on page 58 of the FDA final rule Supplier information concerning what is likely to be present from their raw materials or process can be used to mitigate testing Labeling as Gluten Free is voluntary

6. FDA has asked questions about Gluten in drug products FDA published a notice on December 21, 2011 where they requested information about gluten in drug products which may have created some confusion globally FDA was simply collecting information and many different questions were asked These questions do not indicate the FDA will take any particular actions

7. http://www.regulations.gov/#!dock etDetail;D= FDA-2011- N-0842

8. FDA Notice Some questions requested information about whether FDA should ban the use of wheat derived ingredients in drugs or how they could be labeled Notice was not clear about what type of gluten would be covered – gliadin gluten is the only kind that impacts patients with celiac disease IPEC-Americas prepared and submitted the following comments

9. IPEC-Americas Comments to FDA IPEC-Americas supports the Agency’s intent to provide better options for people who suffer from celiac sprue. We know that it can be very debilitating for the sufferers. However, we believe that the risk to celiac sufferers from excipients in medicinal products is small for the reasons set out in our comments. Nevertheless, IPEC-Americas is open to future and further discussion regarding improvements that can be made which will not be overly burdensome to the manufacturers of either the excipients or medicinal products.

10. IPEC-Americas Comments to FDA Often the modified starches cited in the Federal Register announcement are derived from corn starch or potato starch, and these do not have any gluten issues related to celiac sprue. Even in cases where excipients such as maltodextrins, citric acid, and many others which are derived from botanicals that celiacs are trying to avoid (e.g. wheat/barley/rye), the materials are often highly processed in such a way that effectively and reliably removes or reduces gluten to a very low level (<20ppm gluten remaining in the excipient which is the proposed food definition of gluten free. The gluten level from these excipients would of course be even lower in the final drug product).

11. IPEC-Americas Comments to FDA There has been a lot of work done in the food processing industry regarding allergens, their source, and acceptable levels. There should not be an issue with gluten when wheat is used in processes such as fermentation where a very robust purification step is designed to separate the excipient chemical from other substances in the fermentation media. Take for example, USP ethanol. Ethanol may be derived from many different types of starch, including but not limited to wheat. However, since part of the processing to make pharmaceutical grade ethanol includes a distillation step, and gluten is non-volatile, ethanol is not a source of gluten, regardless of the source of the starch used in the fermentation.

12. IPEC-Americas Comments to FDA For a very small number of drug products that may be formulated with “wheat gluten” as an ingredient [CAS No. 8002-80-0 and GRAS under 21 CFR 184.1322(d)], the excipient listing on the label should clearly disclose “wheat gluten” as an ingredient so that a celiac sufferer can easily avoid use of a product that may cause an undesirable immune response and utilize other therapeutically equivalent products instead. However, given the different levels of plant proteins, specifically gliadins, in the various grains and the differences in the severity of celiac sufferers’ reactions, it would appear to be a difficult task at best to accommodate this segment of the population by trying to remove all exposure to any form of gluten.

13. IPEC-Americas Comments to FDA Reformulating products is extremely expensive, not to mention the associated adjustments to changes in labeling, HACCP plans, processing, sanitation, prior approval supplements, re-qualification and documentation. Avoiding unnecessary and non-value added reformulations will reduce the potential burden on the Agency since reformulation to remove a material and replace it with an entirely different material could require prior approval supplements to be filed. For example, sodium starch glycolate (one of the substances listed in the Federal Register announcement) is included in a significant number of prescription and OTC medicines (probably measured in the hundreds).

14. IPEC-Americas Comments to FDA IPEC-Americas is open to discussing possible alternatives to an ingredient ban such as labeling options or the establishment of limits to support a gluten free definition for drugs. Any decision to label something as gluten free should be voluntary by the manufacturer FDA has not provided any further information about what actions they may take

15. Recommendation to INAME Modify these Argentinian requirements when drafting the regulations to make gluten free labeling a voluntary option if the gluten level is <20 ppm Do not require routine testing unless a gluten free claim is being made on the labeling and the drug product contains some ingredients which may likely contain gluten from their source Limit any gluten controls to ingredients derived from wheat, rye or barley which are likely to contain gluten after their manufacturing process. Do not include oat or corn derived ingredients in the scope of the regulation since these do not contain gliadin gluten

16. Questions/Comments?