Current Good

Manufacturing
Practices for
Nutraceuticals
Current Good Manufacturing Practices for Nutraceuticals
Introduction
There are some basic manufacturing regulations or guidelines that are available to
the nutraceutical industry for producing quality products. However, in most cases
it could be noted that these regulations are not adequate in providing guidance for
the manufacturing facilities, testing, etc. The nutraceutical industry is looking for
more resources from the industry experts, especially from pharmaceutical industry
segments, for valuable guidance to ensure safety of the products delivered to
consumers.
In addition, the utilization of nutraceutical products is increasing as a number
of patients are moving toward alternate medicinal paths from the conventional
medication and prescription drugs, such as multivitamins, anti-diabetics, psoriasis
treatment, etc. Therefore, some of the pharmaceutical industry guidelines can be
adapted by the nutraceutical industry as well. Let us see the potential implementa-
tion of minimal guidelines by taking note of ICH 9, ICH 10, and Quality by
Design (QbD) guidelines. Eventually, regulators around the world sooner or later
will adapt these regulations to ensure the safety of nutraceutical products.
Nutraceutical industries are equally responsible for ensuring the safety of their
consumable products. For example, the combination of nutraceutical and prescrip-
tion drugs can be crucial or often may lead to adverse reactions if not controlled
properly.
The following sections will provide minimum requirements in terms of build-
ing, facilities, quality control, material systems, and documentation requirements.
Please note
Introduction
There are some basic manufacturing regulations or guidelines that are available to the
nutraceutical industry for producing quality products. However, in most cases it could be noted
that these regulations are not adequate in providing guidance for the manufacturing facilities,
testing, etc. The nutraceutical industry is looking for more resources from the industry experts,
especially from pharmaceutical industry segments, for valuable guidance to ensure safety of the
products delivered to consumers.
In addition, the utilization of nutraceutical products is increasing as a number of patients are
moving toward alternate medicinal paths from the conventional medication and prescription
drugs, such as multivitamins, anti-diabetics, psoriasis treatment, etc. Therefore, some of the
pharmaceutical industry guidelines can be adapted by the nutraceutical industry as well.
Let us see the potential implementation of minimal guidelines by taking note of ICH 9, ICH 10,
and Quality by Design (QbD) guidelines. Eventually, regulators around the world sooner or later
will adapt these regulations to ensure the safety of nutraceutical products. Nutraceutical
industries are equally responsible for ensuring the safety of their consumable products. For
example, the combination of nutraceutical and prescription drugs can be crucial or often may
lead to adverse reactions if not controlled properly.
GMPs [1]
5.2.1 Premises [2,5]
The building and other facilities for the manufacturing of nutraceuticals in the
form of powders, tablets, capsules, and liquids should have the following mini-
mum requirements to produce quality products meeting customer requirements
and other regulations [2]. Maintenance activities of plant and buildings should be
planned, conducted, and documented in a manner that prevents contamination
risks. Facilities designed for handling laboratory animals must be isolated from
the manufacturing areas and comply with the relevant regulations in force.
5.2.1.1 Personnel and material flow
Manufacturing and testing facilities should be designed to allow unidirectional
flow of the materials and products throughout the manufacturing, packaging, stor-
age, and testing process. This is required to ensure against the potential mix-ups
64 CHAPTER 5 Current Good Manufacturing Practices for Nutraceuticals
GMPs [1]
5.2.1 Premises [2,5]
The building and other facilities for the manufacturing of nutraceuticals in the
form of powders, tablets, capsules, and liquids should have the following mini-
mum requirements to produce quality products meeting customer requirements
and other regulations [2]. Maintenance activities of plant and buildings should be
planned, conducted, and documented in a manner that prevents contamination
risks. Facilities designed for handling laboratory animals must be isolated from
the manufacturing areas and comply with the relevant regulations in force.
5.2.1.1 Personnel and material flow
Manufacturing and testing facilities should be designed to allow unidirectional
flow of the materials and products throughout the manufacturing, packaging, stor-
age, and testing process. This is required to ensure against the potential mix-ups
64 CHAPTER 5 Current Good Manufacturing Practices for Nutraceuticals
GMPs [1]
5.2.1 Premises [2,5]
The building and other facilities for the manufacturing of nutraceuticals in the
form of powders, tablets, capsules, and liquids should have the following mini-
mum requirements to produce quality products meeting customer requirements
and other regulations [2]. Maintenance activities of plant and buildings should be
planned, conducted, and documented in a manner that prevents contamination
risks. Facilities designed for handling laboratory animals must be isolated from
the manufacturing areas and comply with the relevant regulations in force.
5.2.1.1 Personnel and material flow
Manufacturing and testing facilities should be designed to allow unidirectional
flow of the materials and products throughout the manufacturing, packaging, stor-
age, and testing process. This is required to ensure against the potential mix-ups
64 CHAPTER 5 Current Good Manufacturing Practices for Nutraceuticals

and cross-contamination of the materials. To comply with these requirements, the

firm needs to design the proper physical segregation of material and products in
every stage of manufacturing and storage. For example, adequate design of air-
locks for material and personnel entry would separate GMP areas and non-GMP
areas and would prevent direct access from manufacturing and packaging areas to
the outside environment.
5.2.1.2 Walls and ceiling
The doors, walls, ceilings, and floors should not contain any holes or gaps.
Wooden doors and walls should not be used and material that sheds particles
should be avoided. Ideally, epoxy flooring should be used to permit effective
cleaning. Production areas where dust is generated must have collection systems
and procedures for disposal of collected dust. Any extraction systems used should
avoid potential cross-contamination.
5.2.1.3 Heating, ventilation, and air conditioning system
Adequate ventilation should be provided in manufacturing and packing areas
where there is potential exposure of product to environment and people. As such
there are no regulatory requirements to use terminal HEPA filters in air-handling
units. However, it is recommended to use either HEPA filters or an industry stan-
dard adequate filtration system that is equivalent in multiproduct facilities to
avoid cross-contamination during recirculation of air within the manufacturing
rooms. In absence of proper air filtration systems within the air-handling units,
risk assessment documentation is required to support the design of the HVAC.
It is recommended that lighting used in warehouse and production areas is
made of explosion-proof quality and should be shielded.
5.2.1.4 Utilities
Compressed air and any type of inert gases used in production should be of ade-
quate quality and a procedure should be in place to evaluate the quality of such
air/gas at a specified frequency. Any liquids and gases used in production must
be clearly identified as to their content.
5.2.1.5 Water system
A water system is required for liquid preparations. At a minimum, it is recom-
mended to use purified or distilled water complying with USP standards. The
firm is advised to qualify the water system for its intended purpose. There must
be adequate sanitization practices followed for the water in use. Additionally, a
system should be in place for periodic microbiological and chemical analysis of
the purified water produced in-house or if purchased from external source.
Premises used in the manufacturing of nutraceuticals should be totally segre-
gated and prevented from utilizing the same facilities used for manufacturing of
synthetic hormonal, cytotoxic, and mutagenic drugs; antibiotics; and special types
of products that might lead to potential cross-contamination

GMPs
1 Premises
The building and other facilities for the manufacturing of nutraceuticals in the form of powders,
tablets, capsules, and liquids should have the following minimum requirements to produce
quality products meeting customer requirements and other regulations. Maintenance activities of
plant and buildings should be planned, conducted, and documented in a manner that prevents
contamination risks. Facilities designed for handling laboratory animals must be isolated from
the manufacturing areas and comply with the relevant regulations in force.

1.1 Personnel and material flow

Manufacturing and testing facilities should be designed to allow the materials and products
throughout the manufacturing, packaging, storage, and testing process. This is required to ensure
against the potential mix-ups
and cross contamination of the materials. To comply with these requirements, the firm needs to
design the proper physical segregation of material and products in every stage of manufacturing
and storage. For example, adequate design of airlocks for material and personnel entry would
separate GMP areas and nonGMP areas and would prevent direct access from manufacturing and
packaging areas to the outside environment.

1.2 Walls and ceiling

The doors, walls, ceilings, and floors should not contain any holes or gaps. Wooden doors and
walls should not be used and material that sheds particles should be avoided. Ideally, epoxy
flooring should be used to permit effective cleaning. Production areas where dust is generated
must have collection systems and procedures for disposal of collected dust.
1.3 Heating, ventilation, and air conditioning system
Adequate ventilation should be provided in manufacturing and packing areas where there is
potential exposure of product to environment and people. As such there are no regulatory
requirements to use terminal HEPA filters in air-handling units. However, it is recommended to
use either HEPA filters or an industry standard adequate filtration system that is equivalent in
multiproduct facilities to avoid cross-contamination during recirculation of air within the
manufacturing rooms. In absence of proper air filtration systems within the air-handling units,
risk assessment documentation is required to support the design of the HVAC. It is
recommended that lighting used in warehouse and production areas is made of explosion-proof
quality and should be shielded.

2. Utilities
Compressed air and any type of inert gases used in production should be of adequate quality and
a procedure should be in place to evaluate the quality of such air/gas at a specified frequency.
Any liquids and gases used in production must be clearly identified as to their content.

2.1 Water system

A water system is required for liquid preparations. At a minimum, it is recommended to use
purified or distilled water complying with USP standards. The firm is advised to qualify the
water system for its intended purpose. There must be adequate sanitization practices followed for
the water in use. Additionally, a system should be in place for periodic microbiological and
chemical analysis of the purified water produced in-house or if purchased from external source.
Premises used in the manufacturing of nutraceuticals should be totally segregated and prevented
from utilizing the same facilities used for manufacturing of synthetic hormonal, cytotoxic, and
mutagenic drugs; antibiotics; and special types of products that might lead to potential cross-
contamination.

3. Equipment
There should be a list of processing equipment, including accessories that are in contact with the
product. The equipment used for production, packaging, and storage of a product should be
designed to meet the required quality characteristics and should be located in areas that permit
the installation, operation, cleaning, maintenance, and qualification activities.
The material considered for the design and construction of equipment and accessories that are in
direct contact with components and in-process or finished products should not be reactive and
additive or have any untoward impact on the product quality. Any substance required for the
operation of equipment, such as lubricants, coolants, oils, etc., should not be in contact with the
components of the formula, primary packaging of the product, or the product itself. These sub-
stances should be acquired on the basis of an approved specification.
In the event of such substances coming into contact with the product, they must be at least of
food grade quality and officially approved by the local health authorities. Equipment that is
unsuitable for its intended use should either be removed or clearly labeled for quarantine status.
It is recommended that the computer systems installed on computers to control the
manufacturing process are validated.

4. Personnel
The duties and responsibilities of personnel should be in writing and signed by each employee.

5. Quality assurance
There should be a written document describing the system of quality management according to
established policies and quality objectives. A quality unit should be responsible for approval of
product specifications and standard operating procedures.

 There should be a system and written procedures in place to ensure that all deviations or
non-conformances to specifications, procedures, and methods of analysis are
investigated, evaluated, and documented. Analytical results confirmed to be out of
specification could be considered as deviations or non-conformances.
 There should be a written procedure for handling product complaints. There should be a
written procedure outlining the process of batch record review and release/rejection of
raw materials and finished products.
 It is recommended to have a written procedure that includes identification,
documentation, review, and approval of changes related to manufacturing processes and
methods of analysis. The quality unit is advised to have a system in place for selection,
evaluation, and qualification of suppliers and vendors.
 There should be a system to ensure that all suppliers are assessed before being approved
and included in the list of suppliers of raw materials and packaging materials utilized for
manufacturing of finished products.
 Documentation required:

1. Deviation logs
2. Change control logs
3. List of SOP (SOP inde
4. Master signature list

6. Sanitation program
The manufacturing establishment should have written procedures designed to ensure its safe and
sanitary operation and maintenance. The cleaning procedures should include the cleaning and
sanitizing requirements for the establishment and for all equipment and utensils in it. A list of all
cleaning and sanitizing agents used in the cleaning process should exist, including their
concentrations and uses. The cleaning intervals for manufacturing areas as well as for equipment
should be established.

7. Operations
 There should be established procedures outlining the clear identification and separation
by physical or control systems during manufacturing operations of multiple products in
the same facility.
 There should be adequate measures in the manufacturing area to prevent cross
contamination. Access to the manufacturing areas should be restricted to authorized
personnel only.
 Operations should be carried out according to the production process and should be
registered in controlled documents for each batch or lot of the product.
  The production process should have set parameters and established process controls that
are required to ensure that the product remains within specification as previously
established. The critical steps in manufacturing should be witnessed and records verified
by a second individual.

8. Specifications
Develop and implement written specifications for all raw and finished products. Ensure
specifications are maintained and every change is approved by the quality assurance person prior
to use. Set up and follow written procedures that describe the tests to be conducted to ensure the
identity and purity of finished products. If required, potency must be tested as per predefined,
approved specifications. Procedure should be in place to ensure each lot of raw and finished
products are in compliance with specifications prior to release.

9. Stability
Stability studies should be carried out in at least three pilot batches of the same product that have
been manufactured by applying the same manufacturing method that simulates the process that
will be used in the manufacture of commercial production lots

10. Samples
There should be a written program in place describing the sampling practices followed for
incoming materials and intermediate, in-process, and finished products. The sampling plan
should comply with an international standard, e.g., military standard and ANSI standard. Based
on a specified acceptable level the firm is advised to approve or reject a production lot

11. Records
There should be a written procedure established describing the good documentation practices
that need to be followed during documentation of data records. Data should be recorded by the
person who performed the activity and once the activity is completed. Data recorded should be
clear, legible, and ineradicable. Any correction should be made in such a manner that the original
data is not blacked out. The corrected data should be signed and dated by the person making the
correction. For electronic records, a system should be in place for tracking and for audit
traceability to identify at least the changes made, date of change, and individual who made the
changes.

12. Recall
There should be written procedures that define controls to ensure the effective recall of a
product, including notification to regulatory authorities, if applicable. The procedure should
include the following items:
• Personnel responsible for initiating and coordinating recall activities
• Outlining the steps for implementing a recall
• Distribution records should be maintained for lot traceability
• Notification to regulatory agencies, if applicable
and cross-contamination of the materials. To comply with these requirements, the
firm needs to design the proper physical segregation of material and products in
every stage of manufacturing and storage. For example, adequate design of air-
locks for material and personnel entry would separate GMP areas and non-GMP
areas and would prevent direct access from manufacturing and packaging areas to
the outside environment.
5.2.1.2 Walls and ceiling
The doors, walls, ceilings, and floors should not contain any holes or gaps.
Wooden doors and walls should not be used and material that sheds particles
should be avoided. Ideally, epoxy flooring should be used to permit effective
cleaning. Production areas where dust is generated must have collection systems
and procedures for disposal of collected dust. Any extraction systems used should
avoid potential cross-contamination.
5.2.1.3 Heating, ventilation, and air conditioning system
Adequate ventilation should be provided in manufacturing and packing areas
where there is potential exposure of product to environment and people. As such
there are no regulatory requirements to use terminal HEPA filters in air-handling
units. However, it is recommended to use either HEPA filters or an industry stan-
dard adequate filtration system that is equivalent in multiproduct facilities to
avoid cross-contamination during recirculation of air within the manufacturing
rooms. In absence of proper air filtration systems within the air-handling units,
risk assessment documentation is required to support the design of the HVAC.
It is recommended that lighting used in warehouse and production areas is
made of explosion-proof quality and should be shielded.
5.2.1.4 Utilities
Compressed air and any type of inert gases used in production should be of ade-
quate quality and a procedure should be in place to evaluate the quality of such
air/gas at a specified frequency. Any liquids and gases used in production must
be clearly identified as to their content.
5.2.1.5 Water system
A water system is required for liquid preparations. At a minimum, it is recom-
mended to use purified or distilled water complying with USP standards. The
firm is advised to qualify the water system for its intended purpose. There must
be adequate sanitization practices followed for the water in use. Additionally, a
system should be in place for periodic microbiological and chemical analysis of
the purified water produced in-house or if purchased from external source.
Premises used in the manufacturing of nutraceuticals should be totally segre-
gated and prevented from utilizing the same facilities used for manufacturing of
synthetic hormonal, cytotoxic, and mutagenic drugs; antibiotics; and special types
of products that might lead to potential cross-contamination

and cross-contamination of the

materials. To comply with these
requirements, the
firm needs to design the proper
physical segregation of material and
products in
every stage of manufacturing and
storage. For example, adequate design
of air-
locks for material and personnel entry
would separate GMP areas and non-
GMP
areas and would prevent direct access
from manufacturing and packaging
areas to
the outside environment.
5.2.1.2 Walls and ceiling
The doors, walls, ceilings, and floors
should not contain any holes or gaps.
Wooden doors and walls should not be
used and material that sheds particles
should be avoided. Ideally, epoxy
flooring should be used to permit
effective
cleaning. Production areas where dust
is generated must have collection
systems
and procedures for disposal of
collected dust. Any extraction systems
used should
avoid potential cross-contamination.
5.2.1.3 Heating, ventilation, and
air conditioning system
Adequate ventilation should be
provided in manufacturing and
packing areas
where there is potential exposure of
product to environment and people.
As such
there are no regulatory requirements to
use terminal HEPA filters in air-
handling
units. However, it is recommended to
use either HEPA filters or an industry
stan-
dard adequate filtration system that is
equivalent in multiproduct facilities to
avoid cross-contamination during
recirculation of air within the
manufacturing
rooms. In absence of proper air
filtration systems within the air-
handling units,
risk assessment documentation is
required to support the design of the
HVAC.
It is recommended that lighting used
in warehouse and production areas is
made of explosion-proof quality and
should be shielded.
5.2.1.4 Utilities
Compressed air and any type of inert
gases used in production should be of
ade-
quate quality and a procedure should
be in place to evaluate the quality of
such
air/gas at a specified frequency. Any
liquids and gases used in production
must
be clearly identified as to their
content.
5.2.1.5 Water system
A water system is required for liquid
preparations. At a minimum, it is
recom-
mended to use purified or distilled
water complying with USP standards.
The
firm is advised to qualify the water
system for its intended purpose. There
must
be adequate sanitization practices
followed for the water in use.
Additionally, a
system should be in place for periodic
microbiological and chemical analysis
of
the purified water produced in-house
or if purchased from external source.
Premises used in the manufacturing of
nutraceuticals should be totally segre-
gated and prevented from utilizing the
same facilities used for manufacturing
of
synthetic hormonal, cytotoxic, and
mutagenic drugs; antibiotics; and
special types
of products that might lead to potential
cross-contamination