902 KAR 55:100. Laetrile manufacturing standards.

 

RELATES TO: KRS 217.950, 217.952, 311.950-311.966, 311.991

STATUTORY AUTHORITY: KRS 194.050, 217.950, EO 96-862

NECESSITY, FUNCTION, AND CONFORMITY: KRS 217.950 provides that Amygdalin (laetrile) may be manufactured in this state subject to licensing by the Cabinet for Human Resources and directs the Secretary for Human Resources to adopt administrative regulations which prescribe minimum standards for manufacturers in preparing, compounding, processing, and packaging the substance. The secretary is also directed to establish standards of purity and make periodic tests and inspections of both the facilities for manufacture and samples to ascertain the purity, quality, and identity. Executive Order 96-862, effective July 2, 1996, reorganizes the Cabinet for Human Resources and places the Department for Public Health and its programs under the Cabinet for Health Services.

 

Section 1. Intent. In adopting an administrative regulation relating to the manufacture of Amygdalin (laetrile), the Cabinet for Health Services takes official notice that this substance has not been approved by the Federal Food and Drug Administration and that the interstate shipment of the substance has been held to be illegal. This administrative regulation is adopted in recognition of existing federal restrictions.

 

Section 2. Definitions. (1) "Amygdalin", laetrile means Amygdalin, D-mandelonitrile-beta-D-glucoside-6-beta-D-Glucoside, including all dosage forms.

It includes:

(a) D-Amygdalin; and

(b) D, L-Amygdalin.

(2) "Cabinet" means the Cabinet for Health Services.

(3) "Current good manufacturing practices" means 21 CFR 210.1 to 210.3 - Current Good Manufacturing Practices in Manufacturing, Processing, Packing, or Holding of Drugs and 21 CFR 211.1 to 211.208 - Current Good Manufacturing Practice for Finished Pharmaceuticals adopted by the U.S. Food and Drug Administration.

 

Section 3. Licensing Requirements. (1) A person, partnership, association, corporation, or other business organization shall not manufacture, prepare, or compound Amygdalin in this state without a license from the cabinet.

(2) Application for a license shall be made on Form DCB-1, "Application for License to Manufacture Amygdalin", provided by the cabinet, and shall include the training and experience of personnel and a description of the facilities, equipment, and materials to be used in the manufacture of Amygdalin.

(3) A license shall not be issued to manufacture Amygdalin unless the applicant:

(a) Is of good moral character, or if the applicant is an association or corporation, its officers are of good moral character;

(b) Is in compliance with "Current Good Manufacturing Practices";

(c) Has qualified personnel to perform assigned tasks;

(d) Submits the formula, including all components, involved in the manufacture of the product;

(e) Submits a label which discloses all information required for a prescription drug, including a disclosure of possible side effects;

(f) Is financially responsible; and

(g) Is in compliance with all provisions of this administrative regulation.

 

Section 4. License Expiration; Renewal. (1) Every license issued by the cabinet to manufacture Amygdalin shall expire on June 30 of each year following the date of issuance unless suspended or revoked.

(2) A license shall not be renewed by the cabinet to manufacture Amygdalin unless the applicant is in compliance with the provisions of this administrative regulation.

 

Section 5. Manufacturing Practices. The current good manufacturing practices in manufacturing, processing, packing, or holding of drugs in 21 CFR 210.1 to 210.3 and the current good manufacturing practice for finished pharmaceuticals in 21 CFR 211.1 to 211.208 adopted by the U.S. Food and Drug Administration shall apply.

 

Section 6. Standards of Identity, Purity, and Tests for D-Amygdalin.

(1) Powder form:

(a) Molecular formula: C20H27NO11;

(b) Molecular weight: 457.4;

(c) Description: White powder - melting range: varies with water of crystallization and previous melting;

(d) Solubility: (mg/ml) water 125, ethanol 0.33, ten (10) percent ethanol 20, ether insoluble, methylene chloride insoluble;

(e) Stability:

1. Solution: (10 mg/ml) Determined by gas chromatography of TMS derivative:

pH 6 phosphate buffer

Stable at least twenty-four (24) hours

pH 8 phosphate buffer

No more than fifteen (15) percent L-Amygdalin formed in twenty-four (24) hours

0.1 N HCl

No more than sixty-five (65) percent decomposition in ten (10) minutes

0.1 N NaOH

No more than fifty-six (56) percent decomposition in ten (10) minutes

2. Bulk: A sample stored at sixty (60) degrees Celsius for thirty (30) days showed no degradation as indicated by gas chromatography;

(f) Elemental composition:

Carbon

52.51

Hydrogen

5.95

Nitrogen

3.06

Oxygen

38.48

(g) Water: The compound shall not contain more than six (6) percent water, determined by Karl-Fischer;

(h) Infrared spectrum: The infrared spectrum conforms to reference material;

(i) Ultraviolet absorption: (H2O) a solution has the following absorption peaks (alpha max) and extinction coefficients (E):

Alpha max

E

268 nm

214

262 nm

312

257 nm

287

252 nm

203

208 nm

7400

(j) Nuclear magnetic resonance: (D2O)

 

Chemical

Shift (δ)

Pattern

No.

Protons

Assignment

3.2-5.2

m

14

Glucosyl protons

5.9

s

1

H - C - C = N

7.6

s

5

Phenyl protons

(k) Optical rotation:

Merck Index, 8th Ed. (1968);

 

(l) Gas chromatography:

1. Column: three (3) percent OV-1 on 100/200 Chromosorb W, AW-DMCS in glass column;

2. Oven temperature: 250 degrees to 275 degrees Celsius programmed at one (1) degree per minute;

3. Carrier gas: N2, thirty-five (35) ml. per minute;

4. Sample: TMS-derivative of the sample (Prepare by dissolving one (1) mg. of the sample in five-tenths (0.5) ml. tri-sil with gentle heat.);

5. Detection: Flame ionization at 300 degrees Celsius;

(m) Thin layer chromatography:

1. Adsorbent: SiO2.HF;

2. Solvent system: n-BuOH/HOAc/H2O (6:3:1);

3. Sample applied: 100Υ, 200Υ, (H2O);

4. Detection: UV, I2, KBR Spray;

(n) Purity: The compound shall not contain more than one (1) percent total impurities other than water;

(o) Suggested identity tests: IR, UV & NMR Spectra; and

(p) Suggested assay procedures: Thin layer and gas chromatography.

(2) Tablet form:

TEST

SPECIFICATION

Assay:

Ninety (90)-110 percent of label

HPLC Method

Column-Lichrosorb RP8,

300 mm. x 4 mm.

Mobile phase 25%

CH3OH in H2O

Flow rate - 2 ml./min.

Detector/sensitivity-uv at

254 nm/0.02 aufs

The total of all uv absorbing impurities shall not exceed five (5) of this chromatogram

Disintegration:

Current USP method

100% within fifteen (15) minutes

Dissolution:

Current USP method

100% within thirty (30) minutes

Weight variation

Conforms to current USP

Thin layer chromatography

(Methanol extraction)

Adsorbent: Silica gel GF

Solvent system:

n-BuOH/HOAc/H2O, 4/1/1

Sample applied:

200, 100Υ (MeOH)

References:

D,L-Amygdalin, 100Υ (H2O)

D,L-Amygdalinamide, 2, 4Υ (H2O)

D,L-Amygdalin acid, 3, 5Υ (H2O)

Detection: uv, I2,H2SO4 - charring.

Compares favorably to reference material

 

Section 7. Standards of Identity, Purity, and Tests for D,L-Amygdalin. (1) Powder form:

(a) Molecular formula: C20H27NO11;

(b) Molecular weight: 457.4;

(c) Description: White powder;

(d) Solubility: (mg./ml.) Water 350; Methanol 100+; Chloroform 0.1;

(e) Stability:

1. Solution: A solution of ten (10) mg. in one (1) ml. water shows no degradation as indicated by gas chromatography, after twenty-four (24) hours.

2. Bulk: A sample stored at sixty (60) degrees Celsius for thirty (30) days shows no degradation as indicated by gas chromatography.

(f) Elemental composition:

Carbon

52.51

Hydrogen

5.95

Nitrogen

3.06

Oxygen

38.48

(g) Water: The compound shall not contain more than six (6) percent water, determined by Karl-Fischer;

(h) Infrared spectrum: The infrared spectrum conforms to reference material;

(i) Ultraviolet absorption: (H2O)

Alpha max

E

268 nm

206

262 nm

300

257 nm

280

252 nm

200

(j) Optical rotation:

 

(k) Nuclear magnetic resonance: (D2O)

 

Chemical

Shift (δ)

Pattern

No.

Protons

Assignment

3.2-5.2

m

14

Glucosyl protons

5.9

s

H - C - C = N (L-form)

6.1

s

H - C - C = N (D-form)

7.6

s

5

Phenyl protons

Internal Reference for Assay: Pyrocatechol, 6.9δ;

 

(l) Gas chromatography:

1. Column: three (3) percent OV-1 on 100/200 Chromosorb W-HP glass column, 6' x 2 mm;

2. Carrier gas: N2, forty (40) ml. per minute;

3. Oven temperature: 240 degrees to 275 degrees Celsius programmed at two (2) ml. per minute;

4. Sample: TMS-derivative (Prepare by dissolving one (1) mg. in five-tenths (0.5) ml. tri-sil with gentle heat.);

5. Detection: FID at 280 degrees Celsius;

(m) Thin layer chromatography:

1. Adsorbent: SiO2-GF;

2. Solvent system: n-BuOH/HOAc/H2O) (12:3:1);

3. Sample: 100Υ , 200Υ , (H2O);

4. Detection: I2, UV, (NH4)2SO4 - charring;

(n) Purity: The compound consists of about 50:50 D,L-material. There shall not be more than three (3) percent total organic impurities. The compound shall not contain more than six (6) percent water;

(o) Suggested identity tests:

1. Infrared spectrum;

2. Ultraviolet absorption; or

3. Nuclear magnetic resonance;

(p) Suggested assay procedures:

1. Thin layer chromatography;

2. Karl-Fischer determination; or

3. Gas chromatography.

(2) Sterile injectable form:

TEST

SPECIFICATION

Content uniformity

Ninety (90) to 110 percent of label

HPLC Method

Column-300 mm. x 4 mm. I.D.

Lichrosorb RP8

Mobile phase - 25% CH3OH in H2O

Flow rate - 2 ml./min.

Detector/sensitivity-uv at

254 nm./0.02 aufs.

The total of all uv absorbing

impurities shall not exceed

five (5) percent of this

chromatogram.

Moisture - determine by Karl-Fischer

less than two (2) percent

Weight variation

Conforms to current USP

pH of reconstituted solution

4.0 to 8.0

Color of solution

Colorless

Clarity and completeness of solution

Conforms to current USP

Particulate matter

Conforms to current USP

USP sterility test

Sterile

USP pyrogen test

Nonpyrogenic at 600 mg./kg.

Thin layer chromatography

Adsorbent: Silica gel GF

Solvent system:

n-BuOH/HOAc/H2O, 4/1/1

Sample applied: 400, 200Υ (H2O)

References:

D,L-Amygdalin, 200Υ (H2O)

D,L-Amygdalinamide, 1, 2Υ (H2O)

D,L-Amygdalin acid, 1, 2Υ (H2O)

Detection: uv, I2, 30% H2SO4 - charring.

Compares favorably to

reference material

 

Section 8. Adulterated Amygdalin. Amygdalin shall be adulterated if:

(1) It consists in whole or in part of a filthy, putrid, or decomposed substance;

(2) Produced, prepared, packed, or held under unsanitary conditions where it may have been contaminated with filth or rendered injurious to health;

(3) Its container is composed in whole or in part of a poisonous or deleterious substance which may render the contents injurious to health;

(4) Its strength differs from, or its quality or purity falls below, the standard set forth in this administrative regulation. The determination of strength, quality, or purity shall be made in accordance with the tests or methods of assay in this administrative regulation;

(5) Its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess; or

(6) It has been:

(a) Mixed or packed to reduce its quality or strength; or

(b) Substituted wholly or in part.

 

Section 9. Misbranded Amygdalin. (1) Amygdalin shall be misbranded if:

(a) Labeling is false or misleading in any particular;

(b) In package form, unless it bears a label containing:

1. Name and place of business of the manufacturer, and name and place of business of the packer or distributor, if other than manufacturer; and

2. An accurate statement of the quantity of the contents in weight, measure, or numerical count; reasonable variations shall be permitted;

(c) A word, statement, or other information required by 21 CFR 201.1 to 201.319 and this administrative regulation to appear on the label or labeling is not prominently placed with clarity (compared with other words, statements, designs, or devices, in the labeling) and in terms likely to be read and understood by the ordinary individual under customary conditions of purchase and use;

(d) The label does not state:

1. The common or usual name of Amygdalin;

2. Directions for use; and

3. Warnings against:

a. Use in pathological conditions where a danger to health exists;

b. Use by children where a danger to health exists; and

c. Unsafe dosage, methods, or duration of administration or application;

(e) It has been found by the cabinet to be apt to deteriorate, unless it is packaged in a manner to protect public health, and its label bears a statement of precautions;

(f) The container is made, formed, or filled to be misleading;

(g) It is an imitation of another substance;

(h) It is offered for sale under the name of another substance;

(i) It is dangerous to health if used in the dosage, or with the frequency or duration prescribed, recommended, or suggested in the labeling;

(j) Intended for use by man unless, prior to dispensing, its label bears the statement "Caution: Kentucky law prohibits dispensing without prescription;" or

(k) The label, as originally packed, directs that it is to be dispensed or sold only on prescription, unless dispensed or sold on a prescription of an authorized practitioner, and its label, as dispensed, bears the name and place of business of the dispenser or seller, the serial number and date of the prescription, and the name of the licensed practitioner. Amygdalin prescriptions shall not be refilled.

(2) Amygdalin sold on a prescription of a practitioner shall be exempt from the requirements of this section if:

(a) The practitioner is licensed by law to administer Amygdalin; and

(b) Amygdalin bears a label containing:

1. The name and place of business of the seller;

2. The serial number and date of the prescription;

3. The name of the practitioner; and

4. The name of the patient for whom prescribed.

(3) It is not the intention of subsection (1)(b)1 of this section to require the name and place of business of the wholesaler to appear upon the label of the package.

 

Section 10. Inspections. The cabinet or its duly authorized agent shall have free access at all reasonable times to a factory, warehouse, or establishment in which Amygdalin is manufactured, processed, packed, or held for sale for the purpose of:

(1) Inspecting the factory, warehouse, establishment, or vehicle and all pertinent equipment, finished and unfinished materials, containers, and labeling, to determine if any of the provisions of this administrative regulation are being violated.

(2) Securing samples or specimens of Amygdalin. It shall be the duty of the cabinet to make or cause to be made examinations of samples secured under the provisions of this section to determine if a provision of this administrative regulation is being violated.

(3) Examining or reproducing books, papers, documents, or other evidence pertaining to Amygdalin.

 

Section 11. Detention or Quarantine of Amygdalin if Adulterated or Misbranded. (1) If a duly authorized agent of the cabinet finds, or has probable cause to believe, that any Amygdalin is adulterated or misbranded pursuant to this administrative regulation, the agent shall affix a tag or marking, giving notice that Amygdalin is, or is suspected of being, adulterated or misbranded and has been detained or quarantined. The tag or marking shall be a warning not to remove or dispose of Amygdalin until permission for removal or disposal is given by the agent or the district court. A person shall not remove or dispose of detained or quarantined Amygdalin without permission.

(2) If Amygdalin detained or quarantined under subsection (1) of this section has been found by the agent to be adulterated or misbranded, the agent shall petition the judge of the district court where the Amygdalin is detained or quarantined for an order for condemnation. Nothing in this section shall require the cabinet or its agent to go to court if destruction of the quarantined Amygdalin is accomplished by agreement made in writing with the owner. If the agent has found Amygdalin detained or quarantined is not adulterated or misbranded, the agent shall remove the tag or marking.

 

Section 12. Revocation or Suspension of License. (1) The cabinet may suspend or revoke a license to manufacture Amygdalin for violation of a provision of this administrative regulation after proper notice and an opportunity for a due process hearing.

(2) All administrative hearings shall be conducted in accordance with 902 KAR 1:400.

 

Section 13. Incorporation by Reference. (1) Form DCB-1, "Application for License to Manufacture Amygdalin", revised October 1993, is being incorporated by reference. This form may be inspected, copied or obtained at the Office of the Commissioner for Health Services, 275 East Main Street, Frankfort, Kentucky 40621, 8 a.m. until 4:30 p.m., Monday through Friday.

(2) 21 CFR 201.1 to 201.319, revised as of April 1, 1995, is being incorporated by reference. A copy may be inspected, copied or obtained at the Office of the Commissioner for Health Services, 275 East Main Street, Frankfort, Kentucky 40621, Monday through Friday, 8 a.m. until 4:30 p.m. A copy may also be obtained from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

(3) 21 CFR 210.1 to 210.3, revised as of April 1, 1995, is being incorporated by reference. A copy may be inspected, copied or obtained at the Office of the Commissioner for Health Services, 275 East Main Street, Frankfort, Kentucky 40621, Monday through Friday, 8 a.m. until 4:30 p.m. A copy may also be obtained from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

(4) 21 CFR 211.1 to 211.208, revised as of April 1, 1995, is being incorporated by reference. A copy may be inspected, copied or obtained at the Office of the Commissioner for Health Services, 275 East Main Street, Frankfort, Kentucky 40621, Monday through Friday, 8 a.m. until 4:30 p.m. A copy may also be obtained from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402. (23 Ky.R. 1300; eff. 9-18-96.)