What Are Atypical Actives and How Should They be Controlled What Are Atypical Actives and How Should They be Controlled? GMP and Regulatory Filing Implications Ann Van Meter Business Quality Leader – Dow Pharma & Food Solutions Chair – GMP Committee – IPEC-Americas vanmetma@dow.com www.ipecamericas.org

Atypical Actives Materials known as Atypical Actives have been used in pharmaceutical products for many years These materials are safe and effective in these applications Although these materials can be used as an active, this is not their primary use and is generally a very small percentage of overall sales or volume for a manufacturer They have been brought to the forefront in the last few years due to regulatory initiatives that alter the way these materials have historically been handled

What are “Atypical Actives” There is no official definition – this is part of the problem IPEC suggests: An active pharmaceutical ingredient in a drug product that is primarily manufactured for other uses and for which there are not at least two independent cGMP compliant manufacturers

Other “Definitions” Some “definitions” suggested over the past decade: “Materials that may be classed as excipients or active ingredients depending on specific product usage”- EMA “Substances which have been identified in the Code of Federal Regulations under Part 330 as active ingredients but whose primary industrial usage prior to or during that classification was also categorized as a non-active pharmaceutical or non-pharmaceutical substance”

Characteristics of Atypical Actives An AA may have one or more of the following features: Predominately produced for non-medicinal markets and applications Can often be an excipient Typically does not have any pharmacological activity but is considered an active ingredient by regulators May be the only (non-aqueous) ingredient in a drug product Used in long standing pharmaceutical products and have a good history of patient safety Often used in low value pharmaceutical products, e.g. high volume preparations, generics and OTC (Taken from IPEC EUROPE Q&A on Atypical Actives)

Examples of Atypical Actives Product Category Examples Topical Antitussives Camphor, Menthol, Eucalyptus oil Stimulants Caffeine Acid reducers Bismuth-based antacids, magnesium-based antacids, calcium (carbonate or phosphate) Laxatives Polycarbophil, polyethylene glycol 3350, cellulose, magnesium hydroxide Poison treatment Ipecac syrup, activated charcoal Skin protectants Dimethicone, zinc oxide, petrolatum Acne products Resorcinol, salicylic acid, benzoyl peroxide Astringents Witch hazel, calamine

More Examples Alginic acid Glycerine Phenol Aluminum oxide Honey Pine tar Ammonium acetate Isopropanol “Plant oils” Ammonium chloride Kaolin Polyethylene glycol Amylmetacresol Lanolin Potassium bicarbonate Borax Lemon juice Potassium citrate Butanediol Magnesium carbonate Potassium chloride Calcium carbonate Magnesium hydroxide Potassium phosphate Cellulosics Magnesium phosphate Urea Chorhexidine gluconate “Paraffin” “Vegetable oils” Chorxylenol Pentane Zinc oxide

Challenges with Atypical Actives Likely not manufactured to ICH Q7 guidelines like more traditional API’s Primary use is NOT for drug product Atypical active market is very small compared to other markets for the same product Typically manufactured in a bulk chemical environment GMP standards for primary business may be different (usually excipient (IPEC))

Challenges, continued Biggest gaps are usually in documentation, validation and process control Material compliance (excipient GMP, residual solvents, BSE/TSE, etc.) Additional controls not economically viable Seen by most suppliers as a liability risk with little benefit Stability program – usually stated as “Re-evaluation” vs. Expiry dating

Risks Associated with AAs Most atypical actives present low patient safety risk due to cGMP issues Safe for excipient (or food) use at relatively high levels Many are considered GRAS (Generally Recognized as Safe) Usually used for treating less serious conditions Well known chemical properties Low toxicity Fewer adverse events

Risks to Makers and Users Changes to the regulatory landscape pose potential risks to excipient makers such as: Increased customer expectations (to manufacture to Q7 requirements Increased regulatory scrutiny Increased costs Changes also pose risks for users such as: Makers opt out of the AA market Increased costs (auditing, fees, etc.) Increased need for risk-based decision making

API (Q7) GMPs vs. Excipient GMPs Due to the nature of the manufacturing processes and distribution channels, it would be very difficult and costly to try to use API (Q7) GMPs when manufacturing Atypical Actives Outdoor manufacturing equipment Bulk shipment, terminals, field tanks, etc. Large scale manufacturing equipment Natural raw materials or products The costs rarely would be justified from a business perspective due to the profit margins and market size

New US Regulatory Implications Facility registrations Facility inspections – what GMP will be used Fees – some quite substantial DMF requirements Some excipient manufacturers have a Type 4 DMF, but not all Type 2 DMFs are for Active Pharmaceutical Ingredients Bottom line: Greater level of exposure and risk for excipient manufacturers who happen to have products used as Atypical Actives

IPEC – Initial Concepts for Atypical Actives GMPs aligned with the IPEC-PQG Excipient GMPs should be acceptable (ANSI – IPEC 363 or EXCiPACT GMP Standards) Some additional technical considerations may need to be addressed, examples: Better understanding of specific composition and potential variability Tighter specifications on critical properties where needed (and if capability allows) Improved understanding of stability but not to the same level of stability studies as required for standard APIs Stronger change control and customer notification procedures These are technical requirements, not a higher level of GMP

How to Manage Risks Perform on-site audits of AA manufacturers Mutual understanding of level of GMPs in place Focus on key control points Conduct risk assessments to determine acceptability of the material as an API Conduct full testing of the incoming material Financial incentive (price premium if additional controls are needed) Close working relationship with suppliers to increase understanding Continually assess supplier(s) – Openness and transparency are key to success Agree and document the GMPs that will be implemented for the Atypical Active

Thank You!