technical reference file - cloud object storage · pdf filelast updated: march 2014 capsugel -...

16
Last updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 1 TECHNICAL REFERENCE FILE 4 th Edition

Upload: ledan

Post on 28-Mar-2018

306 views

Category:

Documents


8 download

TRANSCRIPT

Page 1: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

1

TECHNICAL REFERENCE FILE

44tthh EEddiittiioonn

Page 2: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

2

Introduction

The Capsugel Technical Reference File is an assembly of globally recognized technical

information and test methods related to the Vcaps® Plus capsule dosage form. The information in this file can be used by R&D groups who are developing new products and preparing submissions to regulatory agencies. Quality Assurance personnel will find information for supporting and implementing quality systems and manufacturing and materials management staff will find information that is pertinent to running safe and productive operations. The information in this Technical Reference File has been thoroughly screened in order to present accurate and up-to date information. However, it can be expected that 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. As the supplier of Vcaps® Plus capsules as a dosage form, Capsugel will notify customers of any significant changes that would affect the integrity of the product. Typically this is defined as Level II and III changes by the International Pharmaceutical Excipient Council’s Significant Change Guide for Bulk Pharmaceutical Excipients.

Page 3: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

3

The Capsugel Technical Reference File is presented in two sections:

Section 1

Quality Assurance Documents

This section describes the global Quality Assurance documentation provided by Capsugel.

Section 2 Test Methods

This section provides detailed test procedures for assessing capsule integrity and is based, wherever possible, on the latest compendia methods of the regulatory zone of manufacture of the capsules. Capsugel laboratories will apply these compendia methods or their validated alternatives. Whenever a compendia harmonized method exists, Capsugel laboratories will use these or their validated alternatives, where applicable.

Page 4: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

4

Section 1

Quality Assurance Documents

I General Specifications

II Classification of Visual Defects

III Classification of Print Defects

IV Packaging

V Transportation and Warehousing conditions

Page 5: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

5

I General Specifications

Raw material specifications and

Information Capsugel manufactures two piece Vcaps® Plus capsules from Hypromellose that complies with the requirements published in:

the most current edition of the United States Pharmacopoeia (USP) / National Formulary (NF).

the most current edition of the European Pharmacopoeia (EP).

the most current Food Chemical Codex (FCC).

the most current FAO (JECFA monograph).

Composed of Hypromellose,Vcaps® Plus two piece capsules provide a non-animal alternative, without the use of any gelling agents. Small quantities of mold release agents are used in the manufacturing process, and correspond to the description given in the most current edition of the European and US Pharmacopoeia and in the Food Chemical Codex. Capsule shells may also contain opacifiers and coloring agents.

Colorants Capsugel applies, whenever the regulatory status of the dye allows this, colorants and pigments meeting the requirements of the three European, US and Japan food and pharmaceutical regulatory standards. These standards include, where applicable:

The most current edition of the United States Pharmacopoeia (USP) / National Formulary (NF) / Codes of Federal Regulations of the Food and Drug Administration

The most current edition of the European Pharmacopoeia (EP) / Specifications as published in the European legislation for colorants as food additives

The most current edition of the Japanese pharmacopoeia (JP) /Japanese Pharmaceutical excipients (JPE) / Specifications as published in the Japanese legislation for colorants as food additives and Pharmaceutical Synthetic Dyes

Page 6: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

6

I General Specifications (cont.)

Inks The empty capsule can be printed with product logo or company name. The regulations governing printing inks are constantly changing in the global market. Regulations governing use of printing ink colorants should be reviewed for end product acceptance relative to product classification (Pharmaceutical or Nutritional Supplement). Only edible print inks are used by Capsugel for printing.

Manufacturing Process Capsugel capsules are manufactured under controlled climate conditions by a dipping process on high-capacity automatic machines. Imprinting of the pre-closed capsules, if desired by the customer, is undertaken before the capsules are transferred to final packaging. Due to the high quality of its manufacturing conditions, Capsugel, as a standard, does not use sulfur dioxide or ethylene oxide for controlling microbial growth. All of Capsugel’s empty hard capsule manufacturing facilities are ISO 9001 certified. Copies of the certification document are available upon request.

Capsugel manufactures the hard Vcaps® Plus capsules in accordance with the IPEC’s (International Pharmaceutical Excipient Council) Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients.

Batch Definition Capsugel defines a batch as the quantity of product, processed in one process or series of processes. For Capsugel products, a batch of capsules is identified by a lot number.

Capsule Specification Dimensions and tolerances are given in inches and then converted in millimeters (1 inch = 25.401 mm). Unless otherwise indicated, these dimensions and tolerances apply to Vcaps® Plus capsules, at a moisture content of less than 9 % w/w. The dimensions and tolerances are indications for proper filling performance. In case a value would fall outside the prescribed limits, there may be applications for the relevant Acceptable quality levels (AQL).

Page 7: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

7

Vcaps® Plus Capsule Specifications Dimensions and tolerances are given in inches and then converted in millimeters (1 inch = 25.401 mm). These dimensions and tolerances apply to Vcaps® Plus capsules.

Size 00el 00 0el 0el * 0

Weight

Mg 130 122 107 110 96

Tolerance mg ± 10 ± 7 ± 7 ± 7 ± 6

Capacity

Capsule Volume ml 1.02 0.91 0.78 0.78 0.68

Powder density Capsule capacity mg

0.6 g/ml 612 546 468 468 408

0.8 g/ml 816 728 624 624 544

1 g/ml 1020 910 780 780 680

1.2 g/ml 1224 1092 936 936 816

Length of the capsules parts (body and cap)

Body Inches 0.866 0.796 0.795 0.826 0.726

Tolerance Inches ±0.018 ±0.018 ±0.018 ±0.018 ±0.018

Body mm 22.20 20.22 20.19 20.98 18.44

Tolerance mm ±0.46 ±0.46 ±0.46 ±0.46 ±0.46

Cap Inches 0.509 0.462 0.460 0.472 0.422

Tolerance inches ±0.018 ±0.018 ±0.018 ±0.018 ±0.018

Cap mm 12.95 11.74 11.68 11.99 10.72

Tolerance mm ±0.46 ±0.46 ±0.46 ±0.46 ±0.46

External diameter **

Body Inches 0.322 0.322 0.289 0.290 0.289

Body mm 8.18 8.18 7.34 7.36 7.34

Cap Inches 0.336 0.336 0.301 0.301 0.300

Cap mm 8.53 8.53 7.65 7.66 7.64

Overall closed length ***

Inches 0.995 0.917 0.925 0.953 0.854

Tolerance inches ±0.012 ±0.012 ±0.012 ±0.012 ±0.012

mm 25.3 23.30 23.5 24.2 21.70

Tolerance mm ±0.30 ±0.30 ±0.30 ±0.30 ±0.30

* Europe only

** All tolerances ± 0.002 inches or ± 0.06 mm. The data above is an indication of the external diameter and

should not be considered as an accept/reject criteria (due to the tapered shape of the capsule and the difficulty to measure the exact diameter). These data can be used for specifying packaging material dimensions.

*** The overall closed length specifications are for filled capsules locked in the ring-in-ring position. It must be emphasized that the overall length of a filled capsule can still vary to a small extent with regard to filling content and filling machine adjustment.

As Capsugel continues to develop and improve this product, these specifications will remain subject to

continued review.

Page 8: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

8

Vcaps® Plus Capsule Specifications Dimensions and tolerances are given in inches and then converted in millimeters (1 inch = 25.401 mm). These dimensions and tolerances apply to Vcaps® Plus capsules.

Size 1 1el 2 3 4

Weight

Mg 76 81 61 47 38

Tolerance mg ± 5 ± 5 ± 4 ± 3 ± 3

Capacity

Capsule Volume ml 0.50 0.54 0.37 0.30 0.21

Powder density Capsule capacity mg

0.6 g/ml 300 324 222 180 126

0.8 g/ml 400 432 296 240 168

1 g/ml 500 540 370 300 210

1.2 g/ml 600 648 444 360 252

Length of the capsules parts (body and cap)

Body Inches 0.654 0.697 0.601 0.535 0.480

Tolerance Inches ± 0.018 ± 0.018 ± 0.018 ± 0.018 ± 0.018

Body mm 16.61 17.70 15.27 13.59 12.19

Tolerance mm ± 0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46

Cap Inches 0.385 0.413 0.352 0.318 0.284

Tolerance inches ± 0.018 ± 0.018 ± 0.018 ± 0.018 ± 0.018

Cap mm 9.78 10.49 8.94 8.08 7.21

Tolerance mm ± 0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46

External diameter **

Body Inches 0.261 0.261 0.239 0.219 0.199

Body mm 6.63 6.63 6.07 5.57 5.05

Cap Inches 0.272 0.272 0.250 0.229 0.209

Cap mm 6.91 6.91 6.35 5.82 5.32

Overall closed length ***

Inches 0.765 0.804 0.709 0.626 0.563

Tolerance inches ± 0.012 ± 0.012 ± 0.012 ± 0.012 ± 0.012

mm 19.40 20.40 18.00 15.90 14.30

Tolerance mm ± 0.30 ± 0.30 ± 0.30 ± 0.30 ± 0.30

** All tolerances ± 0.002 inches or ± 0.06 mm. The data above is an indication of the external diameter and

should not be considered as an accept/reject criteria (due to the tapered shape of the capsule and the difficulty to measure the exact diameter). These data can be used for specifying packaging material dimensions.

*** The overall closed length specifications are for filled capsules locked in the ring-in-ring position. It must be emphasized that the overall length of a filled capsule can still vary to a small extent with regard to filling content and filling machine adjustment.

As Capsugel continues to develop and improve this product, these specifications will remain subject to continued review.

Page 9: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

9

II Classification of Visual Defects

Statistical Inspection Capsugel Vcaps® Plus capsules are statistically controlled to ensure batch conformance to the quality parameters described below. Both acceptance sampling and process signal capturing can be used. An acceptance sampling plan is used based on the ANSI / ASQ Z 1.4-2008, “Sampling Procedures and Tables for Inspection by Attributes.” A normal inspection level, single sampling plan is used.

Acceptable Quality Level (AQL) The definition of AQL in ANSI / ASQ Z 1.4-2008: “The AQL is the maximum percent nonconforming (or the maximum number of non conformities per hundred units) that, for purposes of sampling inspection, can be considered satisfactory as a process average.”

Average Outgoing Quality Limit (AOQL) The AOQL is “the maximum of the AOQs (average outgoing qualities) for all possible incoming qualities for a given acceptance sampling plan.” This definition is in ANSI / ASQ Z 1.4-2008.

Definition of Visual Defects Visual defects are classified according to the following definitions (specific criteria for classification are described overleaf):

Critical visual defects: defects which cause loss of container properties of the capsule or cause a low dosage weight of the capsule or cause a major filling machine stoppage or production operation delay.

Major visual defects: defects which may cause problems in the filling operation such as non-opening, failure to rectify or incorrect closure.

Minor visual defects: defects which do not affect the filling operation but detract from the visual or cosmetic appearance of the product.

AQL and AOQL Percentages The AQL’s indicated below should be verified on a random composite sample withdrawn from √N + 1 cartons, where N is the number of cartons in the shipment. Sample size is determined according to the sampling procedures of ANSI / ASQ Z 1.4-2008.

Defect

Group

Critical

Defects

Major

Defects

Minor

Defects

Lot Size > 500,000 > 500,000 > 500,000

Sample Size

1250 1250 1250

Accept 0 1 7

Reject 1 2 8

AQL 0.01% 0.04% 0.25%

AOQL 0.029% 0.067% 0.36%

Page 10: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

10

II Classification of Visual Defects

Defect Reason for classification

Critical defects Oil hole Leakage

Scrape hole Leakage

Uncut Low dosage risk

Cracked Leakage

Short body* Low dosage

Double dip Bushing blockage

Telescoped Rectification channel blockage and bushing blockage

Mashed Rectification channel blockage

Trims Rectification channel and bushing blockage

Splits* Leakage

Large Strings Rectification channel blockage

Major defects Loose pieces Non-rectification

Closed capsule Non-separation

Bad join Non-separation

Double caps Non-rectification

Rough cuts (major)* Non-separation

Collet pinches (major)* Non-separation

Punched ends (major)* Non-rectification/non-separation

Thin spots Potential Leakage

Short cap* Potential risk in joining

Long body* Punched end during closure

Long cap* Punched end during closure

Grease Visual Appearance

Minor defects Splits (minor)*

Rough cuts (minor)* Visual appearance defects with no risk of defects during filling operation.

Collet pinches (minor)*

Punched ends (minor)*

Bubbles*

Wrinkles*

Star ends*

Specks*

Scrapes

Grease marks*

Strings

*Detailed criterion specified separately

Page 11: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

11

II Classification of Visual Defects

Defect Dimensional Limit Criteria for Classification

Short body

Length of body is 2 mm shorter than specified length (for body the SNAP-FIT ring is absent).

Split

A split in the cap reaching the SNAP-FIT groove is defined as a critical defect. Smaller splits are defined as minor defects. Splits on capsule body greater than 1 mm are critical defects for all sizes.

Rough cut

Irregular cuts which result in abnormal separation resistance are defined as major defects. Rough cuts greater than 1 mm and not causing separation problems are classified as minor defects.

Collet pinches

Major collet pinches are classified based on abnormal separation resistance. Longitudinal pinch marks greater than 4.0 mm in length for sizes greater than and equal to 1 and greater than 3.0 mm in length for sizes smaller than 1 are classified as minor defects.

Punched ends

Major punched ends are classified based on abnormal separation resistance or difficult rectification. Indentations greater than 3.0 mm diameter for sizes greater than 1 and greater than 2.0 mm for sizes smaller than and equal to 1 are defined as minor defects.

Short cap

Length of cap is 1 mm shorter than specified length.

Long body or cap

Length of cap or body is 1 mm greater than specified length.

Page 12: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

12

II Classification of Visual Defects

Defect Dimensional Limit Criteria for Classification

Bubbles

Bubbles greater than 1.0 mm are defined as minor defects. Three or more bubbles in a capsule greater than 0.5 mm are also defined as minor defects.

Wrinkles

Longitudinal wrinkles greater than 3 x 2 mm are classified as minor defects.

Star ends

Top stellated wrinkles greater than 4.0 mm diameter for sizes greater than and equal to 1and 3.0 mm for sizes smaller than 1 are classified as minor defects.

Specks

Specks of 1 mm or more in size are judged as minor defects.

Grease Marks

Marks which can be recognized at a distance of 30 cm under natural light with an area of 3.0 mm2 are judged as minor defects.

Strings

Strings at the cutting edge of 3 mm or more for sizes greater than and equal to 1 and 2 mm or more for sizes smaller than 1 are judged as minor defects. Large strings which will block the rectification channels are judged as critical defects.

Page 13: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

13

III Classification of Print Defects

Statistical Inspection Capsugel Vcaps® Plus capsules are statistically controlled to ensure batch conformance to the quality parameters described below. Both acceptance sampling and process signal capturing can be used. An acceptance sampling plan is used based on the ANSI / ASQ Z 1.4-2008, “Sampling Procedures and Tables for Inspection by Attributes.” A normal inspection level, single sampling plan is used.

Acceptable Quality Level (AQL) The definition of AQL in ANSI / ASQ Z 1.4-2008: “The AQL is the maximum percent nonconforming (or the maximum number of non conformities per hundred units) that, for purposes of sampling inspection, can be considered satisfactory as a process average.”

Average Outgoing Quality Limit (AOQL) The AOQL is “the maximum of the AOQs (average outgoing qualities) for all possible incoming qualities for a given acceptance sampling plan.” This definition is in ANSI / ASQ Z 1.4-2008.

Definition of Print Defects Print defects are classified according to the following definitions (specific criteria for classification are described overleaf):

Critical print defects: unprinted capsules with complete absence of the logo.

Major print defects: print defects which result in illegibility and non-identification of the printing logo.

Minor print defects: print defects which do not affect the legibility or identification of the printing logo but detract from the visual appearance of the capsule.

AQL and AOQL Percentages The AQL’s indicated below should be verified on a random composite sample withdrawn from √N + 1 cartons, where N is the number of cartons in the shipment. Sample size is determined according to the sampling procedures of ANSI / ASQ Z 1.4-2008.

Defect

Group

Critical

Defects

Major

Defects

Minor

Defects

Lot Size > 500,000 > 500,000 > 500,000

Sample size 1250 1250 800

Accept 0 2 21

Reject 1 3 22

AQL 0.01% 0.065% 1.50%

AOQL 0.029% 0.11% 1.8%

Page 14: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

14

III Classification of Print Defects

Defect Description

Critical defect Unprinted Capsules with complete absence of the logo

Major defect Illegible All types of defects resulting in the illegibility and non

identification of the printing logo.

Unrectified print Cap and body print logo are reversed

Minor defect Print line - Line through print logo

Print interruption - partially missing

- poor cover-up

Smeared - print smeared

- roller background

Off-register - print off-register

- print off-set

Ink spots

Defect Defect example Criteria for Classification

Unprinted

Critical defect: Capsules with complete absence of logo.

Multiple print Major Major Major defect:

Capsules with print in multiple positions, resulting in illegibility of the print logo.

Print interruption Major Minor Major defect:

- partially missing

Capsules with at least half of the lettering missing,

- poor cover-up resulting in non-identification. Minor defect:

Capsules with at least half of one letter missing but where the logo remains legible.

Page 15: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

15

III Classification of Print Defects

Defect Defect example Criteria for classification

Smeared Major Minor Major defect:

- print smeared

Capsules with extensive smearing, resulting in - roller background Illegibility of the logo.

Minor defect: Capsules with smearing, resulting in partial

illegibility of the logo.

Off-register Major Minor Major defect:

- print off-register

Capsules with letters missing, resulting in a non-identification of the logo.

Minor defect: Capsules with at least half of one letter missing

but where the legibility of the logo remains intact.

- print off-set Major Minor Major defect:

Capsules with at least half the logo letter height missing due to logo misplacement.

Minor defect: Capsules with an incomplete logo letter height

but where the logo remains legible.

Ink spots Major Minor Major defect:

Capsules with ink specks 5.0 mm or greater for sizes greater than and equal to 2 and 4.0 mm or greater for sizes smaller than 2. Minor defect: Capsules with ink specks 1.0 mm or greater .

Print line Minor Minor defect:

Capsules with line through the printing logo. Legibility is not affected.

Page 16: TECHNICAL REFERENCE FILE - Cloud Object Storage · PDF fileLast updated: March 2014 Capsugel - Technical Reference File - Vcaps®Plus capsules 2 Introduction The Capsugel Technical

Last updated: March 2014

Capsugel - Technical Reference File - Vcaps®Plus capsules

16

IV – Packaging

In order to protect Capsugel hard Vcaps® Plus capsules from large variations in the surrounding relative humidity, standard packaging consists of protective, food grade antistatic bags inside robust cardboard cartons. Each bag is tamper-evident sealed ensuring integrity of the product.

V - Transportation and Warehousing Conditions

In spite of the protective packaging used, care must be taken during transportation that Vcaps® Plus capsules are not left on a loading dock or in an unattended truck for several hours during warm weather. The ideal storage conditions are a relative humidity of 50% and a temperature of 20°C. Capsugel recommends that our capsules be stored in the closed containers in which they are dispatched in areas were the ambient temperature is 15°C to 25°C and the relative humidity 35% to 65%. Prolonged storage in areas outside these conditions may cause capsules to soften and loose their shape or to become difficult to separate, with the results that problems may be encountered during the filling operations. In order to prevent such problems arising, it is recommended that containers of capsules are not stored for prolonged periods of time directly on the floor. They should also be stored away from radiators and direct sunlight. Storage close to potential sources of water damage should also be avoided.

If these recommended precautions for storage conditions and warehousing are observed, capsugel Vcaps® Plus capsules will remain in good condition. Capsugel continues a global stability program and maintains data supporting five years shelf life of our capsules.