technical reference file • addendum · 2019-05-17 · revised october 2014 capsugel - technical...

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This document contains Capsugel proprietary information and should not be copied or distributed without consent of your Capsugel representative.

Technical Reference File • Addendum •

Dry Powder Inhaler Capsules

Americas

Hard Gelatin Capsules

2nd edition

Revised October 2014 Capsugel - Technical Reference File – Addendum - Dry Powder Inhaler Capsules

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Introduction The Capsugel Technical Reference File is an assembly of globally recognized technical information and test methods related to the hard capsule dosage form. Aligned with the Capsugel DPI technology platform, designed to respond to specific drug delivery performance needs that meet the expectations of pharmaceutical companies as well as responding to patient needs, specific specifications apply to our DPI capsules.

These DPI capsule specifications apply in addition to the specifications and information available in the Technical Reference File of Capsugel’s Coni-Snap® Hard Gelatin Capsules, as applicable.*

The information in this Technical Reference File Addendum has been thoroughly screened in order to present accurate and up-to date information. Changes and additions will continue to take place. In order to assure our customers that the most accurate information is available to support their Quality Systems, recipients of the Capsugel Technical Reference File can contact their Capsugel Territory Sales Manager or Customer Service Representative for the latest version that includes updates/changes that have occurred since the time of this publication.

*Note: These specifications apply to the Capsugel site located in Greenwood, SC (USA)


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Dry Powder Inhaler Capsules

Tests and Specifications

Specific Specifications

Dry Powder Inhaler Capsules* Test Specification Method Reference

Coni-Snap® Hard Gelatin Capsules

Lubricant content Less than 500 ppm WI-CHEM-351 Total Aerobic Microbial Count Less than 100 cfu per gram WI-0115 Total Yeast and Mold Count Less than 10 cfu per gram WI-0116 Specified micro-organisms: Bile-Tolerant Gram-Negative

Absence in 1 gram WI-0117

*Specific to Empty Hard Gelatin Capsules manufactured in Greenwood, SC (USA)


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WI-CHEM-351

Lubricant content – Alternative method Specification The lubricant content is less than 500 ppm. Reagent/Equipment HPLC Phenomenex Kinetex™ C-18 Column, 4.6 4.6 mm ID, 100 mm Length (Phenomenex Part No. 00D-4462-E0) LPM Oil Analytical Balance 100 mL volumetric flasks 10 mL volumetric flasks Disposable syringes and syringe filters with a porosity of 0.45 microns or smaller Cellulose extraction thimbles, 33 mm x 80 mm, Whatman Cat. No. 2800338 250 mL – 500 mL Round bottom flask Soxhlet Extractor Water cooled condenser Acetone Acetonitrile Blender (to grind capsules) 200 mL Beakers Hot Plate

Method Setup the LPM Oil method on the HPLC using the following parameters:

Mobile Phase: 75% Acetone: 25% Acetonitrile

Flow Rate: 2 mL/minute

Injection Volume: 20 µL

Detection: UV @ 209 nm

Run Time: 5 minutes Place the acetone in Solvent A container and the acetonitrile in Solvent B container. To prepare the standards, transfer 500 +/- 50 mg of LPM Oil to a 100 mL volumetric flask. Add acetone to the flask until approximately ¾ full and sonicate for 10 minutes. (Note: LPM Oil is not completely soluble in acetone. The triglyceride portion has dissolved when the LPM Oil no longer appears to be liquid and small semisolid pellets remain on the bottom of the flask.)

After sonication is complete, add acetone to the meniscus. Calculate the standard concentration by dividing the mass of LPM Oil (W) by the total volume (100) = W/100. Filter the standard solution though a syringe filter with a porosity of 0.45 microns or smaller into an HPLC 2 mL sample vial. To prepare the samples, grind slightly more than 10 grams of capsules in a blender. Transfer approximately 10 grams of ground capsules, accurately weighed, to a cellulose extraction thimble. Add 100 mL of acetone to a round bottom flask and assemble the extraction apparatus as shown below.

To extract the LPM Oil from the capsules, reflux the acetone in the extraction apparatus for 2 hours. (Note: Reflux time starts when acetone first begins to condense in the Soxhlet extractor.) Once the apparatus has cooled and the acetone is no longer boiling, disassemble the apparatus. Transfer the acetone in the round bottom flask and Soxhlet extractor to a 250 mL beaker. Slowly evaporate the acetone extracts on a hot plate to a volume of 5 mL or less. Take care to avoid evaporating extracts to dryness. If extract is


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accidently evaporated to dryness, the sample must be re-extracted. Carefully, transfer the remaining acetone to a 10 mL volumetric flask. Rinse beaker with small amounts of acetone and transfer the rinses solution to the 10 mL flask. Then fill the flask to the meniscus with acetone. Filter the acetone extract through a syringe filter with a porosity of 0.45 microns or smaller into an HPLC 2 mL sample vial. Analyze the standards and samples using the HPLC equipment. Make six injections of the standard. The %RSD of the standard peak area must not exceed 5%.

If the system suitability passes with a %RSD not exceeding 5%, then inject the samples and calculate the % LPM Oil using the following calculation:

%100W

mg1000

g1mLx10C

A

A

OilLPM % standard

sample

Where Asample & Astandard are the peak areas of the sample & standard, C is the standard concentration (in mg/mL), & W is the sample weight (in grams). Reference Capsugel method

Use 1st major peak

after 1 minute for

quantitation.


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WI-0115 and WI-0116

Total Aerobic Microbial Count – Total Yeast and Mold Count Specification Less than 100 Total Aerobic Microbial Count (cfu) per gram Less than 10 Total Yeast and Mold Count (cfu) per gram

Reference USP37/NF32 Harmonized methods – USP Chapters <61> and <62> Microbiological examination of non-sterile products: Microbial enumeration tests


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WI-0117

Bile-Tolerant Gram Negative Bacteria Specification Absence in 1 gram

Reference USP37/NF32 Harmonized methods – USP Chapters <61> and <62> Microbiological examination of non-sterile products: Microbial enumeration tests


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Example – Empty Hard Gelatin Capsules - DPI

CERTIFICATE OF ANALYSIS

The capsules are produced under very carefully controlled conditions. Controls are performed continuously throughout the process and guarantee that capsules conform to the highest quality standards. The capsules described below conform to the specifications as defined in the current edition of the Capsugel Technical Reference File for Empty Hard Gelatin Capsules.

PRODUCT DESCRIPTION Empty Hard Gelatin Capsules – DPI

Customer: Customer name Capsugel Lot Number: 7XXXXXXX Product Name: Customer Reference: Product Code: Product Size: Size 3 Manufacturing date: 10 Jan 2014 Type: Coni-Snap Expiration date: 10 Jan 2019 Capsugel Part Number: BODY CAP Code: 43.000 Code: 0998 Name: Natural Transparent Name: White Opaque IMPRINTING Axial print logo can be on body or cap Logo: Design / Roll Code: Ink:

Body Composition Cap Composition

GELATIN qsp100% TITANIUM DIOXIDE GELATIN

1.9573% qsp 100%

Due to the nature of raw materials, their sourcing, and technology improvements, the color composition data indicated are target values and actual values may vary to insure the consistency of lot color. Capsugel supports the expiry date if recommendations for warehousing and transportation are observed (recommended: 15°C - 25°C and 35% - 65% relative humidity)

Ingredient / Reference E Nr C.I. Nr Function Regulatory References TITANIUM DIOXIDE E171 77891 OPACIFIER EU 231/2012, 21CFR,EP,JP,USP/NF

STRUCTURE EP,JP,USP/NF GELATIN ANALYTICAL and MICROBIOLOGICAL DATA

Characteristics Test Method Units Specifications Results Identification of gelatin WI-0107A Positive pass * Identification of TiO2 WI-0110A Conforms to composition pass * Sulfated ash WI-0108A % Less than 5 1 * Arsenic WI-0104D ppm Less than 1 0.000 * Lead WI-0104B ppm Less than 1 0.043 * Cadmium WI-0104A ppm Less than 0.5 0.001 * Mercury WI-0104C ppm Less than 0.1 0.035 * Sulfur dioxide WI-0093A ppm Less than 50 2.7 * Disintegration time WI-0101A min/sec Less than 15:00 2:56 * Lubricant content WI-CHEM-351 ppm Less than 500 202 Loss on drying WI-0119 % Between 13.0 to 16.0 14.6 Average Weight WI-0118 Between 45 and 51 47.4 Total Aerobic Microbial Count WI-0115 cfu /g Less than 100 < 10 Escherichia coli WI-0111 Absence in 1 gram pass * Salmonella WI-0113 Absence in 10 grams pass * Staphylococcus aureus WI-0114 Absence in 1 gram pass Pseudomonas aeruginosa WI-0112 Absence in 1 gram pass Total Yeast and Mold Count WI-0116 cfu/g Less than 10 < 10 * Bile-Tolerant Gram Negative Bacteria WI-0117 Absence in 1 gram pass * Reduced frequency testing


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CERTIFICATE OF

ANALYSIS

Customer: Capsugel Lot

Number:

7XXXXXXX

Physical Characteristics

Appearance - Clean empty capsules, meeting the specified requirements of color and size.

Odor - Free of disagreeable odor.

Tests for odor, solubility and acidity conform to Japanese Pharmacopoeia requirements.

The reported disintegration time is subjective, and is provided to indicate Pass/Fail status for 15 minutes.

Capsugel hard gelatin capsules are meeting <2 ppm Chromium as defined in the Chinese pharmacopoeia for Vacant Gelatin Capsules.

In accordance with ICH Q3C residual solvent guideline, Class 3 Solvents may be used according to good manufacturing practices such that their cumulative value does not exceed 5000ppm or 0.5%, under option 1 as defined in ICH Q3C, USP<467>, and EP General Text 5.4.

TSE/BSE Regulations Capsugel can use blends of several pharmaceutical gelatins. When bovine gelatin is used by Capsugel, it is in full compliance with all pharmaceutical regulatory statutes. Specifically, Capsugel fully complies with the following where applicable:

Commission Directive 2003/63/EC, compliance is demonstrated by “Certificates of Suitability”.

Regulation (EC) No 853/2004 on specific hygiene rules for food of animal origin.

Regulation (EC) No 999/2001 as regards specified risk material, Commission Regulation (EC) No 722/2007.

United States FDA September 1997 Guidance for Industry.

United States FDA - 21 CFR Parts 211, 226, 300, 500, 530, 600, 895, and 1271 related to Use of Materials Derived from Cattle in Medical Products.

United States FDA - 21 CFR Parts 189 and 700 related to Use of Materials Derived from Cattle in Human Food and Cosmetics.

Japanese Ministry of Health, Labor Welfare (MHLW) - “Food Sanitation Law”, No. 10 in MHLW notification on January 16,2004.

Japanese Ministry of Health, Labor and Welfare (MHLW) –Notification No. 210 of MHLW, issued on May 20, 2003.

The raw material is derived from healthy animals slaughtered in a slaughterhouse, which have been inspected by an official veterinarian and have been deemed fit for human consumption.

Preservative Status:

Capsules are manufactured without the addition of preservatives

Capsules are manufactured without ethylene oxide treatment or (Ethylene Oxide is not used for terminal microbial control of empty capsule)

Capsules are manufactured without irradiation treatment

CAPSUGEL – Greenwood Quality Assurance 535 N Emerald Road Greenwood, SC 29646

Toll Free: 800-845-6973 Phone: 864-942-3863 Fax: 864-942-4029

Approver: Approval Date & Time:


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Revision Control Revision number Date Change Made

1st Edition February 2014 Initial version issue

2nd

Edition October 2014 Updated USP/NF references

Added Lubricant Content Method WI-CHEM-351

QUAKERTOWN,PA

BEND,OR

MEXICO CITY, MEXICO

PUEBLA,MEXICO

TAMPA,FL

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RIO DE JANEIRO, BRAZIL

GREENWOOD,SC

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This document contains Capsugel proprietary information and should not be copied or distributed without consent of your Capsugel representative.

technical reference file • addendum · 2019-05-17 · revised october 2014 capsugel - technical...

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