1. 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

2. 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

3. 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

4. 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”

5. 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)

6. 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

7. 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

8. 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))

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. Thank You!