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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 nonreactive, 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 oneand-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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Critical defects
Cracked/split
Double dip
Holes
Mashed
Short body
String on end
telescoped
Trims,
Uncut cap/body

Major defects
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

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

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
Major
1250
Minor
1250

0
1
0.01
0.029
1
2
0.04
0.067
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
Unprinted

Major defect
Illegible print

Minor defect
Multiple print
Broken letter
Smudged print

Off register
Ink spot/ink lines
Light/dark print

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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
Major
1250
Minor
1250

0
1
0.01
0.029
2
3
0.065
0.110
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
Unlocked cylindrical capsules
Cap
As per approved colour shade
Colour
Body
As per approved colour shade
Description
Print message: Cap
As per approved artwork
text, colour &
Body
As per approved artwork
orientation
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)
0
0
Loss on drying (at 105 C 1 C for minimum
Between 13.0% - 16.0% w/w
4 hours or to constant weight)
Size
000
00el
00
0xel
0el+
0el
0
Target
163
130
119
109
108.3 104
96
Within
151.6
120.9
110.7
101.4
100.7
96.7
89.3
7%
Range
Average weight of
174.4 139.1 127.3 116.6 115.9 111.3 102.7
capsule shells in mg
(Wt.
of
100
Size
1el
1
2el
2
3
4
5
capsules/100)
Target
81
76
68.4 63
50
39
28
75.3
70.7
63.6 58.6
46.5 36.3
26.0
Range
86.7
81.3
73.2 67.4
53.5 41.7
30.0
PURITY
No foreign odour after 24 hours when kept at a
Odour
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.acgassociatedcapsules.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

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SUMMARY OF DIMENSIONS FOR ACG ASSOCIATED CAPSULES HARD GELATIN CAPSULE SHELLS
CAPSULE SIZE

00el

0xel

0el+

0el

1el

2el

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

570

492

468

468

408

324

300

246

222

180

126

60

760

656

624

624

544

432

400

328

296

240

168

80

1. CAPACITY
Body Volume (ml)

Capsule capacity (mg) for powder density


822
612
0.6 g / cc
1096

816

1370

1020

950

820

780

780

680

540

500

410

370

300

210

100

1644

1224

1140

984

936

936

816

648

600

492

444

360

252

120

Avg. wt in mg

163

130

119

109

108.3

104

96

81

76

68.4

63

50

39

28

Tolerance in %

13

13

11.8

11.8

12

11.7

10.7

10.5

9.8

9.7

8.1

7.2

6.2

Tolerance (mm)*
Body Nominal
(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

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
25.9
length (mm)
0.4
Tolerance (mm)*

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

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


9.96
8.55
Cap Nominal (mm)

8.55

7.66

7.66

7.66

7.66

6.93

6.93

6.37

6.37

5.85

5.33

4.91

0.8 g / cc
1.0 g / c.c
1.2 g / cc
2. WEIGHT

3. LENGTH
Cap Nominal (mm)

Tolerance (mm)*
Body
Nominal
(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

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