a primer on hard gelatin capsule manufacturing

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ACG Associated Capsules A Primer on Hard Gelatin Capsule Manufacturing Understanding what goes into making high-quality empty hard gelatin capsules.

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Introduction Hard gelatin capsule shells are used as soluble containers for incorporation of drugs or nutritional supplements, usually in the form of powders, pellets or granules in the healthcare industry. They are commonly intended for oral administration having its advantages over other dosage forms that are used widely by pharmaceutical companies to develop different medicaments and ensure stability of the product throughout the shelf life. Since it serves as a major excipient for the manufacture of pharmaceutical products, the quality attributes of hard capsule shells is very vital for performance and stability of the final product. Pharmaceutical products are categorized as high quality and high risk product administered to fight various types of acute and chronic illnesses where the performance of the product should be reproducible every time it is administered. The capsule shell consists of two cylindrical parts i.e. the cap and body; both are open at one extreme. Other extreme of both is hemispherical; the open end of cap overlaps the open end of body and maintains a closure with a typical lock system. Hence, it is very important that the product achieves the label claim as set forth and is not contaminated and readily available to the patients. Benchmarking of developments and manufacturing processes in the pharmaceutical industry as against other industries led to the concept of Quality by Design or QbD. Over the past few years, QbD has gained considerable acceptance throughout pharmaceutical industry and has been successfully applied. The key quality attributes of capsules that determine the process ability on the high speed filling machine are the dimensional characteristics and weight variability. The potential variations of empty hard capsules as an input material and its potential impact on finished product quality has been studied and high consistency within the specification of the critical quality parameters is confirmed. Annual product quality review needs to be performed using defined sampling size against set of verification criteria. The built-in quality approach begins at the development stage of new product where even factors impacting the performance of hard capsules i.e. formulation, filling machine type, etc., is given due consideration. The selection of proper raw material, the process validations and stability studies are to be conducted for suitability. The process conditions should be maintained along with appropriate in-process quality checks. Final release of product can be done by QA after product and document review. The data on process capability, trends of quality parameters, technical specification and the evaluation procedure should be maintained and submitted based on the current level of quality standards.

Manufacturing of Hard Gelatin Capsule Shells Raw Materials The manufacture of hard gelatin capsule shells is by physical molding process where gelatin & water are the basic raw materials required. Colorants & opacifiers are optional and are used as per requirement. Gelatin Gelatin from bovine source is the main raw material used in the manufacturing of hard capsule shells. Bovine gelatin used is derived from bones and hides of healthy animals that have been certified as fit for human consumption by a veterinary official at slaughtering. The tissues used in the manufacture of gelatin are free from specified risk material. It should be ensured that bovine gelatin conforms to TSE/BSE regulation as applicable to the country of use. All gelatin used must confirm to applicable pharmacopoeia and food regulation like:

Regulation (EC) No 999/2001

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Regulation (EC) No 853 2004 Commission directive 2003/63/EC and European Pharmacopoeia - 1483 evidenced by

certificate of suitability. USFDA Sept 1997 Guidance to industry for sourcing and processing of gelatin to reduce the

potential risk posed by BSE in FDA regulated product. USFDA 21 CFR parts 189, 589, 700 pertaining to prohibited cattle material in human food,

drugs and cosmetics and animal feeds. USFDA 9 CFR part 94.18 pertaining to restriction on important edible products from

ruminants due to BSE. USFDA 9 CFR part 94.19 on gelatin from ruminants that have not been in any region where

BSE exists Food Colors Food colorants applicable to the regulatory standards must be used for the manufacturing of hard gelatin capsules. Colors that require FDA approval as per customer intent bear the FDA lot number. Colors not requiring FDA approval, as per local regulation or customer, should be accompanied by certificate of analysis complying with applicable standard. Stock solutions of food colors are prepared and the concentration of solution is checked by QC, and suggested for any corrections required. As per the recipe, known concentration of color stock solutions are added to mucilage to achieve the required shade conforming to the primary master sample. Purified Water Purified water conforming to applicable pharmacopoeia is to be used for preparing mucilage for capsule manufacturing. The pre-treatment of water is carried out with sodium hypochlorite and flocculating agents. The pre-treated water is filtered through multigrain, sand filters softened and demineralized. Demineralized (DM) water is monitored for conductivity and pH. DM water plant is interlocked for regeneration when pH and conductivity is out of limit. UV lamps are installed at critical points for control of microbial contamination. The DM water is pumped through 0.2 filters. The distribution and storage is non-corrosive stainless steel. The purified water is maintained at temperature of 82+ 2 degrees and is under continuous hot loop circulation. In addition, raw water is checked for hardness daily. User points are also sampled and tested for Micro, hardness, pH, conductivity, potability on a daily and weekly basis. Material Movement After receiving the material, it is quarantined bearing appropriate sticker and the lot information. Containers are sampled as per the sampling plan by QC under reverse laminar air flow one at a time and labeled. The sampled material is tested for compliance to the defined pharmacopoeial and in house specifications. The approved materials are identified by appropriate approved labeling which mentions the analytical report number and the reassessment date. Storage of quarantine and approved material is segregated. Only raw materials, which are approved by QC and within the shelf life, are dispensed and issued to production. The dispensing is carried out based on system generated recipe for the particular batch; this is done on suitable calibrated weighing scale. Product is identified by labels, identification cards, and tags at all stages of production. Raw materials that do not confirm to specifications are labeled with rejected label and stored segregated in secured manner to prevent inadvertent use till material is returned back to the vendor. All stages of bulk manufacturing area are designated for in-process rejects and are kept under control.

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PROCESS CONTROLS

Figure-1 - Schematic of Raw Material Movement Prior to Dipping

Bulk Manufacturing Mucilage Preparation The mucilage is prepared in stainless steel jacketed vessels with impeller for uniform mixing of the additives in controlled environment conditions. The clear transparent gelatin solution is withdrawn in feed tanks that are also stainless steel jacketed vessel. Each color shade can be identified by unique identification number and the recipe is stored in the system. The colorants are added as per the recipe in the feed tank and the final shade is approved by QA. The temperature of gelatin solution is maintained at 50 +1 degree throughout the process. The gelatin solution should be converted within 18 hours to ensure there is no risk of microbial growth in the solution. Adequate in-process checks are done to ensure right quality of mucilage is issued for manufacturing. Equipment surfaces that come in contact with in-process material/finished product, should be non-reactive, non-corrosive and non-additive. The pin bars have typical lock pattern and vents engraved on them for proper locking and to facilitate displacement of air at the time of closing on high-speed filling machines. The cap of capsule also has pre-locks to reduce possibility of premature separation of cap and body during transportation and conveying prior to filling. The hard gelatin capsule machine comprises four main sections:

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Dipping Section The dip baths hold the gelatin solution for molding. The design of the dip bath is developed to ensure proper weight spread. The dip baths central and parellal functions are monitored to ensure equal picking up of gelatin at all the four corners of the dipping section. The pin bars undergo one-and-a-half rotation to ensure uniform distribution of gelatin solution in the dome portion. The pin bars are reconditioned and polished before re-dipping in the gelatin solution. Drying Section The dipped pin bars form stacks and are carried on conveyor to drying section. There are different drying hoods in the drying section. The temperature and relative humidity in each drying zone is controlled by maintaining the dew point for proper drying of capsule. Auto Head Section The dried shells are carried on a conveyor into the auto head section. The dried capsules are stripped, cut and joined in this section. The cap and body are held separately in the collet ring and are cut with specially-designed ceramic blades to the required length. The frequency of blade checking and replacement is defined and closely monitored. Air Transfer System The capsules manufactured are transferred to moisture stabilization chamber through venturi. The capsules are flushed with controlled air for stabilization of moisture. The capsules, after joining, are ejected on series of mechanical sorter where defects generated as a virtue of process are trapped and prevented from further processing. Sorters such as: Diametrical Sorter: The diametrical sorter is a go-no-go sieve with openings of the size of cap diameter, allowing any damaged or disfigured capsules are trapped. Nail Bed Sorter: Usually, the ring created after the cap and body are cut is sucked through vacuum. However, if not trapped by vacuum, these rings can be trapped in the bed of nails installed. The nail bed sorter also catches any loose caps or bodies. Loose Body Sorter: This sorter consists of a rotating disc with spacers between two discs, exactly the size more than the outer diameter of body and slightly less than the inner diameter of cap. Due to the rotational movement, only good capsules get carried over to the hopper of venturi. All loose bodies are collected in rejection tray. All the above sorters are placed in series at the ejection chute to confirm the defective capsules are trapped before further processing. The entire manufacturing is auto process and there is no manual intervention for any intermediate processing. After moisture stabilization in the chamber, the capsules are again passed through the loose cap / double cap sorter, diametrical sorter and loose body sorter. In addition, all capsules are passed through metal detector before collection in shipper boxes; ensuring 100% quality check

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Figure-2 - Schematic for Manufacturing Process Flow

In Process Quality Assurance (IPQA) IPQA checks for compliance include:

Colour shade and opacity Pre-lock length Moisture percentage. Pull test Brittleness Powder stickiness test for clear transparent capsules Dimensional parameters after every 4 hours

Assessment of Visual Defects All the boxes are sampled and checked for visual defects and categorized based on severity of defect for capsule as a dosage form. Based on defects observed in the sample, all the boxes are graded by in-process QC inspectors.

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Table-1 - Classification & Types of Manufacturing Defects Categorization of defects

Lot Size 500,000 and above Sample size Acceptance

Number Rejection Number

AQL% AOQL%

CAPSULE DEFECTS Critical 1250 0 1 0.01 0.029 Major 1250 1 2 0.04 0.067 Minor 1250 7 8 0.25 0.360

Table-2 - Indication Acceptable Quality Limits (The AQLs indicated above could be verified on a composite random sample drawn from k +1

cartons in the shipment, where k = number of cartons in the shipment.)

Printing and Packing Imprinting of Capsules Capsules can be printed in linear or circular form, with or without orientation, and in single, double & even four-colour printing. Pharmaceutical grade ink is used for printing. The capsules are printed in the printing head. Ink is applied to engraved printing roller. It is roto-gravure type continuous printing operation, where the print message with ink is transferred from printing roller to rubber roller and then onto the capsule. Printed capsules are online passed through loose body sorter and the diametrical sorters to entrap any loose body and mashed capsules generated during printing operations. The printing machines are equipped with electronic camera system to detect foreign capsules in the lot. Assessment of Printing Defects Printing defects are evaluated based on sample size and acceptance number derived from the ISO 2859 Part I using single sampling Plan-I. 100% of boxes printed are sampled and checked for printing defects. Accordingly all boxes are graded by IPQA. Critical defect Major defect Minor defect Unprinted Illegible print Multiple print

Broken letter Smudged print

Off register Ink spot/ink lines Light/dark print

Critical defects Major defects Minor defects Cracked/split Double dip Holes Mashed Short body String on end telescoped Trims, Uncut cap/body

Bad join Closed capsules Double cap Grease/oil rings Long body Long cap Loose pieces Major collet pinch Major punched dome Major rough cut Short cap Thin spots

Bubbles Dirt marks Minor collet Pinch Minor punched dome Minor rough cut Minor splits Scrapes/scratches Specks Star ends Strings Wrinkles

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Table-3 - Classification & Types of Printing Defects

Categorization of defects

Lot Size 500,000 and above Sample size Acceptance

Number Rejection Number

AQL% AOQL%

PRINT DEFECTS Critical 1250 0 1 0.01 0.029 Major 1250 2 3 0.065 0.110 Minor 1250 21 22 1.0 1.2

Table-4 - Indication Acceptable Quality Limits (The AQLs indicated could be verified on a composite random sample drawn from k +1 cartons in

the shipment, where k = number of cartons in the shipment. Corresponding AQL & AOQL values are also provided therein.)

Figure-3 - Schematic for Printing Process

Quality Control Testing program is in place that encompasses specifications, sampling plans and test procedures for raw materials, packaging materials, in-process materials and finished products. The quality control lab is equipped to perform the testing. This assures the product meets the required standard in terms of Quality, Purity and Safety. Preparatory tests are performed to ascertain suitability of microbial tests applied.Once the packing of product is completed and confirmed in the system, complete document review and product review is carried out by the QA team and final confirmation for the release of product is done in system after complete review.

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Figure-4 - Schematic for Final QC Procedure

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Table-5 - Specification of Hard Gelatin Capsule Shells as per international capsule manufacturers TEST SPECIFICATIONS IDENTIFICATION

Description

Unlocked cylindrical capsules

Colour Cap As per approved colour shade Body As per approved colour shade

Print message: text, colour & orientation

Cap As per approved artwork

Body As per approved artwork

Identification of gelatin Positive for gelatin Identification of colorants/iron oxides Conform to approved composition Identification of Titanium Dioxide Conform to approved composition PERFORMANCE Disintegration time in water at 37 20 C Maximum 15 minutes (with guided disc) Loss on drying (at 1050C 10C for minimum 4 hours or to constant weight) Between 13.0% - 16.0% w/w

Average weight of capsule shells in mg (Wt. of 100 capsules/100)

Within 7 %

Size 000 00el 00 0xel 0el+ 0el 0 Target 163 130 119 109 108.3 104 96

Range 151.6 - 174.4

120.9 - 139.1

110.7 - 127.3

101.4 - 116.6

100.7 - 115.9

96.7 - 111.3

89.3 - 102.7

Size 1el 1 2el 2 3 4 5 Target 81 76 68.4 63 50 39 28

Range 75.3 - 86.7

70.7 - 81.3

63.6 - 73.2

58.6 - 67.4

46.5 - 53.5

36.3 - 41.7

26.0 - 30.0

PURITY

Odour No foreign odour after 24 hours when kept at a temperature between 300C & 400C SAFETY Sulphated ash Maximum 5 % w/w * Arsenic Maximum 1 ppm Lead Maximum 1 ppm Lubricant content Maximum 0.5 % w/w Sulphur dioxide Maximum 50 ppm Mercury Maximum 0.1 ppm Cadmium Maximum 0.5 ppm MICROBIAL LIMITS Total aerobic microbial count Maximum 500 cfu / g Yeast & mold Maximum 100 cfu / g Escherichia coli Absent / 1 g Salmonella Absent / 10 g Pseudomonas aeruginosa Absent / 1 g Staphylococcus aureus Absent / 1 g

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================================================================================= About ACG Associated Capsules ACG Associated Capsules (ACG ACPL) is one of the largest manufacturers of two-piece hard gelatin capsules in the world. To complement its wide range of hard gelatin capsules, ACG ACPL also manufactures capsules from 100% natural plant source (Naturecaps), capsules for filling liquids and pastes (FlofitTM), circular two-colour printed capsules (Brandshield 3600), four-colour circular-print anti-counterfeit capsules (Brandshield 4C), clinical trial capsules (Clinicaps) and many more. Catering to the global pharmaceutical and dietary supplement industries in over 100 countries, ACG ACPL produces over 60 billion capsules annually through three plants in and around Mumbai, India, another plant in Ludbreg, Croatia, and a new state-of-the-art facility in Indore, India. Visit www.acg-associatedcapsules.com for more information. Why Us?

Over five decades of experience with hard capsule production Versatile product portfolio; capsules made from a variety of raw materials Capsules available in a widest range of 14 sizes; from 000 to 5 (including special sizes) Up to four-colour linear or circular printing on capsules Sophisticated, state-of-the-art manufacturing facilities All regulatory approvals, certifications and standards are maintained, which includes US FDA,

EU, Japan, GMP, WHO, ISO, Pharmacopoeia, Kosher and Halal and more Warehousing facilities in multiple global locations Global sales and service support


SUMMARY OF DIMENSIONS FOR ACG ASSOCIATED CAPSULES HARD GELATIN CAPSULE SHELLS CAPSULE SIZE 0 00el 0 0xel 0el+ 0el 0 1el 1 2el 2 3 4 5 1. CAPACITY Body Volume (ml) 1.37 1.02 0.95 0.82 0.78 0.78 0.68 0.54 0.5 0.41 0.37 0.3 0.21 0.1

Capsule capacity (mg) for powder density 0.6 g / cc 822 612 570 492 468 468 408 324 300 246 222 180 126 60

0.8 g / cc 1096 816 760 656 624 624 544 432 400 328 296 240 168 80 1.0 g / c.c 1370 1020 950 820 780 780 680 540 500 410 370 300 210 100

1.2 g / cc 1644 1224 1140 984 936 936 816 648 600 492 444 360 252 120

2. WEIGHT Avg. wt in mg 163 130 119 109 108.3 104 96 81 76 68.4 63 50 39 28

Tolerance in % 7 7 7 7 7 7 7 7 7 7 7 7 7 7

3. LENGTH Cap Nominal (mm) 13 13 11.8 11.8 12 11.7 10.7 10.5 9.8 9.7 9 8.1 7.2 6.2 Tolerance (mm)* 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Body Nominal (mm) 22.2 22.2 20.2 21.8 21 20.3 18.5 17.7 16.6 16.7 15.2 13.6 12.2 9.3

Tolerance (mm)* 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 4. OVERALL CLOSED LENGTH Nominal Joined length (mm) 25.9 25.5 23.5 24.8 24.2 23.2 21.4 20.4 19.3 19.3 17.8 15.8 14.4 11.4

Tolerance (mm)* 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 5. NORMAL OUTSIDE DIAMETER

Cap Nominal (mm) 9.96 8.55 8.55 7.66 7.66 7.66 7.66 6.93 6.93 6.37 6.37 5.85 5.33 4.91

Tolerance (mm)* 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 Body Nominal (mm) 9.61 8.22 8.22 7.34 7.34 7.34 7.34 6.63 6.63 6.08 6.08 5.57 5.06 4.65

Tolerance (mm)* 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.03

a primer on hard gelatin capsule manufacturing

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