# Presentation: 159454

## Quality Control and Quality Assurance of Botanicals

- Complementary and Alternative Medicine in Chronic Liver Disease
- August 22-24, 1999
- Natcher Conference Center, NIH
- Yuan-yuan Chiu, Ph.D.
- Acting Director, Office of New Drug Chemistry,
-     Center for Drugs Evaluation & Research, FDA
- Chair, CDER Botanical Working Group

## Classification of Botanical Products

- Based on “intended use”
- Food - consumed for taste, aroma, or nutritive value (orally administered)
- Dietary supplement - supplement to diet with effects on structure and function of human body
- Drug - diagnose, cure, treat, mitigate, or prevent disease

##            Botanical productsDietary Supplement		Drugs

- Foods
- Food GMP
- Structure and function claims
- FDA to prove unsafe
- Efficacy - disclaimer
- Authenticity needed
- Potency not an issue
- Quantity required
- Oral administration

- Drugs (OTC or Px)
- Drug GMP
- Disease claims
- Safety proven
- Efficacy proven
- Authenticity needed
- Potency critical
- Consistency required
- Oral or non-oral

## QA/QC for Dietary Supplement

- Not adulterated
- Not misbranded
- In compliance with food GMPs and to-be-published dietary supplement GMPs
- Adhered to emergency permit controls for control of microbial hazards

## Adulterated Food Including Dietary Supplement 

- If it contains any added poisonous or deleterious substance which may render it injurious to health, or which is unsafe
- If it consists in whole or in part of any filthy, putrid, or decomposed substance
- If it is prepared, packed or held under insanitary conditions

## Adulterated Food Including Dietary Supplement (QA/QC)

- If any valuable constituent has been in whole or in-part omitted or abstracted therefrom
- If any substance has been substituted wholly or in part

## Dietary Supplement Labeling (QA/QC)

- Name and quantity of each ingredient (standard of identity)
- Total weight of each ingredient (quantity of contents)
- plant part used (common or usual name)

## Botanical Drugs

- Old drugs (before 1938) - generally recognized as safe and effective (GRASE)
- OTC monograph drugs  GRASE,
- Used to a material extent and material time in US
- Petition FDA with documentation of S/E and identity of the active substance(s)
- Meet public and/or FDA standards

## Botanical New Drugs

- New drugs
- OTC or Px dispensing
- Demonstrating safety and effectiveness for its intended use
- Submitting chemistry, manufacturing and controls information
- Manufacturing under drug GMPs
- Approval by FDA prior to initiation of clinical trials or marketing

## Definition of Botanical Drugs

- Derived from algae, fungus, or one or more plants
- Crude extracts
- Not highly purified
- Multiple components in mixtures

## Characteristics of Purified Drugs

- Chemically defined, impurities present at extremely small quantity, <1% total
- Toxicity often the intrinsic property of one chemical entity, the active moiety

## Issues on Botanical Drugs

- Standardization based on relevant and/or irrelevant marker(s) - false assurance?
- Contribution to efficacy and/or toxicity not limited to marker(s)
- Efficacy and toxicity not always assured from batch to batch of a product from a manufacturer, or of the same product from different manufacturers

## Critical Elements to Assure Quality and Consistency

- Strict quality controls of each plant raw material(s)
- Tight in-process controls
- Vigorous process validation
- Appropriate and adequate plant testing of product (drug substance) and dosage form using validated test methods

## Plant Raw Material Controls

- Genius/species identification
- Macroscopic/microscopic tests
- Genotypic (DNA) analysis
- Chemical tests
- Growth location
- Harvesting time
- Processing of plant part(s)
- Storage and shipping condition
- Qualification of new supplier(s)

## Plant Products (Drug Substance)Process Controls and Validation

- Dried powder, juice, tea, tincture, standardized extract, essential oil, isolated components
- Grinding, pulverizing, extraction, etc
- Solvent(s)
- Temperature/time
- In-process controls
- Yield

## Characterization of Plant Product(Drug Substance)

- Chemical classes of the mixture
- Proteins, fatty acids, polysaccharides, sterols, saponins, terpene lactones, alkaloids, etc
- Individual chemical constituents in each class
- GC, LC, TLC, LC-MS, etc.
- Identification of active constituents or biologically relevant markers, and/or determination of biological activity(ies)

## QC Tests for Plant Product(Drug Substance)

- Identification - multiple fingerprints
- Strength - weight
- Assay
- Biological activity (potency)
- Amount of clinically relevant markers
- Impurities and contaminates
- Pesticides, endogenous toxins, exogenous toxins, radioactive materials, heavy metals, microbials

## QC Tests for Dosage Forms(Drug Product)

- Identification
- Assay
- Content uniformity
- Dissolution
- Degradation products
- Others unique to a dosage form

## Stability of Botanicals

- Forced degradation under stressed conditions
- Changes in fingerprint profiles
- Validity of the analytical methods

## Lot-to-Lot Consistency

- Equivalence between clinical material and to-be-marketed product
- Equivalence before and after manufacturing changes
- Starting material
- Supplier
- Process
- Formulation

## Reference Standards for QC Tests

- Plants
- Extracts
- Individual constituents (actives, markers, degradants)
- Manufacturer’s or public standard

## Summary

- A botanical drug is uniquely defined by
- The plant raw material(s) used
- The manufacturing process used to prepare the botanical drug substance
- The chemical characteristics (e.g., the chemical constituents present) of the botanical drug substance and drug product

## Summary

- Botanical Drugs should be standardized based on
- Identity - multiple fingerprints
- Potency and strength (amount)
- Purity (impurities/contaminates)
- Consistency qualitatively and quantitatively
- Stability

## Summary

- Equivalence between products of different firms is not deemed
- Products derived from the same plant may not be assumed to be therapeutically the same when their chemical components and composition are different and when actives and toxic components are not identified

## Other Issues on Botanical Drugs

- FDA is preparing a guidance document
- FDA is revising its regulations on fixed combination drugs to exempt certain botanicals
- FDA is finalizing its rules on the structure/function claims for dietary supplements, including definition of diseases

## Other issues on Botanical Drugs

- IND exemption not applicable to dietary supplements tested for diseases claims
- CFR 312.2(b) *Exemption* (1) The clinical investigation of _a drug product that is lawfully marketed in the United States_ is exempt from the requirements of this part...

## Other Issues on Botanical Drugs

- FDA is willing to advise sponsors in developing IND programs for botanicals
- FDA welcomes applicants to submit NDAs or OTC petitions
- FDA review staff are available for pre-submission consultations