Regulatory considerations for manufacturing,packaging and labeling of pharmaceuticals in USA. PDF/PPT

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Regulatory considerations for manufacturing,
packaging and labeling of pharmaceuticals in USA.

Packaging System

Packaging system composed of container and Closure. It may
also include several layers of Protection for the pharmacopoeial
preparation Along with any sealing device, delivery device And

labeling and packaging inserts. 1


• Primary Container

• Primary container is the component of packaging System that maintains the
direct contact with the Product. This is to protect the product from
Environmental hazards during shipping and Handling.
Secondary Container

• Secondary container is which encloses one or More primary containers. It is
used to carry the Required label and also to hold the primary Container
together with the delivery device or Other add-on feature. This also provides
the Protection to the components during the Handling.
Container for pharmaceutical use is an article which holds or intended to
contain and protect the drug. This may be in direct contact with the product.
Closure is a part of container. 2


• Packaging Material

Any material including printed material, employed in the packaging of pharmaceutical product excluding any

outer package used for transport or shipment.Packaging Information to be provided in the Submission

The information included in the application should be enough to provide the evidence that the container closure

system and its components are suitable for its intended use. Type and detailing of the information depends on the

dosage form and its route of administration, unlike liquid orals solid orals are in less contact with the container

closure system. So, the information provided in the application for liquid preparations should contain more

detailed than solid oral preparations.

• A detailed description about the container closure system should be included in the Chemistry, Manufacturing

and Controls (CMC) section of application. Along with this the given information should be provided by

applicant for each individual component of packaging system.

• A) Identification by product name, product code (if available), the name and address of the manufacturer, and

a physical description of the packaging component such as, type, size, shape, and color. 3


• B) Identification of the materials of construction should be identified by a specific product
designation (code name and/or code number) and the source (name of the manufacturer). Alternate
materials of construction should also be indicated. Recycled plastic is not acceptable for preparing
primary component.

• If it is used in secondary component the justification for its quality attributes should be provided.

c) Description of any operations or preparations that are performed on a packaging component by the
applicant (such as washing, coating, sterilization, or depyrogenation) should be included.

d) To ensure the safety and post approval consistency in safety, the complete chemical composition of
each material used in packaging system should be provided.

e) Different types of test are required to perform to qualify and characterize the material. The
complete description about the test methods, acceptance criteria, reference standards and test results
should be provided.

f) To address safety and compatibility, the results of extraction/toxicological evaluation studies
should be provided for drug products that are likely to interact with the packaging components and
introduce extracted substances into the patient. 4


• G) Stability study of the drug product in the proposed container closure system
should be conducted. The container closure system should be clearly identified in
the study protocol. The container closure system should be monitored for signs of

The evaluation of packaging system should be included in the protocol and the
observations, results and any corrective actions should be included in the stability

h) Generally tests provided in pharmacopoeia are sufficient for establishing the
characteristics of the particular material. If any non-pharmacopoeial method is used,
applicant should provide justification for the use of the test, a complete and detailed
description of how the test was performed, and an explanation of what the test is
intended to establish.

• 5


• i) If any equivalent method available in the pharmacopeia, comparative data and the supporting data for the suitability of
the method should be provided

Suitability refers to the ability of the container closure system to work according to its intended use.

• It should adequately protect the dosage for,

• It should be compatible with the dosage form,

• It should be composed of materials that are considered safe for use with the dosage form and the route of administration.

• If the packaging system has a performance feature in addition to containing the product,

the assembled container closure system should be shown to function properly.

A container closure system should provide the dosage form with adequate protection from factors that can cause
degradation in the quality of that dosage form during its shelf life. Common causes of such degradation are: exposure to
light, loss of solvent, exposure to reactive gases (e.g., oxygen), absorption of water vapor, and microbial contamination
Packaging components which are compatible with the drug substance or product packed in it, 6


• not interact sufficiently to cause unacceptable changes to the quality of
either product or packing material. The construction material should not
leach any undesirable materials to which the patient will be exposed when
treated with the drug product.

• This is specially considered in case of materials which are in direct contact
with the product, it is also taken into consideration in such a case where
the material may migrates into the product. In case of parenterals,
opthalmics, and inhalations an extensive study of the construction material
is necessary.

• This involves the extraction study to know the type of chemicals that will
migrate from the material into dosage form and toxicology study to know
the effect of the substance and determine its safety levels.The information
related to suitability such as, description of tests, methods, acceptance
criteria, reference standards, and validation information for the studies
should be provided in the application. The information should be
submitted directly in application or indirectly byreferencing to a Drug
Master File (DMF). If it is referenced to a DMF, a letter of authorization
must be submitted along with application. 7


• Quality Control of Packing Components

The application should contain the information Related to the quality control measures taken to
Ensure the quality of the components. These Quality control measures are required to ensure The
consistency in the quality after the approval. Majority of considerations are given to physical And
chemical attributes. Variation in the physical parameters considered Important if it can affect the
quality of the dosage Form. Chemical composition may change affect The safety of the packaging
component. Any Change in the composition may result in Extraction of new chemicals or change in
the Quantity of the extract.

Secondary packaging components give the Additional protection to the dosage form. Such as, Protection from
light, protection from excessive Solvent loss protects from excessive moisture and Reactive gases permeation,
protection from rough Handling and protect from microbial Contamination. In the application very less
Information should be provided about secondary Packaging components as they were not in direct
Contact with the dosage form
Tests to be performed on Packaging System
Glass Containers
1.Light Transmission Test
Chemical Resistance
Chemical resistance of the container is tested for Glass containers by using following tests
a.Powdered glass test
b.Water attack test 8


Plastic Containers
Light transmission test
Water vapor permeation test
Physicochemical tests
Biological tests
In vitro biological tests
O Agar diffusion test
O Direct contact test
O Elution test
In vivo biological tests
O Systemic injection test
O Intra cutaneous test
O Implantation test 9


• Labeling
• Labeling is the best source of information Regarding the medication. Even though

written Information and oral communication with Medical practitioner may be
available, the label Should fulfil the obligations for safe and effective Use of
medicine.Some of the factors lead to Medication errors, that include but not
limited to Are given here,Missing of key information like product Name, strength,
and dosage form Key information doesn’t appear on the same Field of vision i.e.,
the information is not Readable without having to turn the container Labels
which looks similar among multiple Strengths of same products and similar labels
Among different products Labels which are cluttered by extraneous text Or
distracting images and graphics 10


• Text is difficult to read because of typical Font size, type and overlapping of the text.Principal display panel
should contain the most prominent information like proprietary name, established name, product strength,
route of administration, warnings. Other information like Rx only statement, net quantity statement,
manufacturer name, and logo should not compete with important information and it is better placed on the
side panel. USFDA recommends that the text on the label should be in the same direction, same field of vision,
and surrounded by adequate white space to improve the readability. The size of the label should be adequate
to accommodate the important information on PDP of the label. Font size and style of the text should be easy
to read and recommended size is 12-points whenever label size permits. Contrast of the text and background
colour should be appropriate to afford adequate legibility of the text. Abbreviations, synonyms and acronyms
which may lead to misinterpretation are not used. 11


• Legislation and regulations for import, manufacture, distribution and sale of cosmetics in USA and

Importation into Canada

5 Subject to section 9, no person shall import into Canada for sale a cosmetic the sale of which in Canada
would constitute a violation of the Act or these Regulations.

6 An inspector may examine and take samples of any cosmetic sought to be imported into Canada.

7 Where an inspector examines or takes a sample of a cosmetic pursuant to section 6, he may submit the
cosmetic or sample to an analyst for analysis or examination.

8 Where an inspector, on examination of a cosmetic or sample thereof or on receipt of a report of an
analyst of the result of an analysis or examination of the cosmetic or sample, is of the opinion that the
sale of the cosmetic in Canada would constitute a violation of the Act or these Regulations, the inspector
shall so notify in writing the collector of customs concerned and the importer. 12


9 (1) Where a person seeks to import a cosmetic into Canada for sale and the sale would constitute a violation of the Act or
these Regulations, that person may, if the sale of the cosmetic would be lawful in Canada after relabelling or modification of
the cosmetic, import the cosmetic into Canada on condition that(a)9 (1) Where a person seeks to import a cosmetic into
Canada for sale and the sale would constitute a violation of the Act or these Regulations, that person may, if the sale of the
cosmetic would be lawful in Canada after relabelling or modification of the cosmetic, import the cosmetic into Canada on
condition that(a)he gives to an inspector notice of the proposed importation; and(b) the cosmetic will be relabelled or
modified under the supervision of an inspector in such a manner as to enable the sale of the cosmetic to be lawful in
Canada.he gives to an inspector notice of the proposed importation; and (b) the cosmetic will be relabelled or modified
under the supervision of an inspector in such a manner as to enable the sale of the cosmetic to be lawful in Canada.

(2) No person shall sell a cosmetic that has been imported into Canada under subsection (1) unless the cosmetic is relabelled
or modified in accordance with the Act and these Regulations within three months after its importation. 13


• Sales

• 12 No person shall sell a cosmetic if any label or advertisement of the cosmetic contains any
symbol or statement that implies that the cosmetic has been compounded in accordance with a

• 13 No person shall sell a cosmetic recommended for removing stains from the teeth that has a
measure of acidity greater than that represented by a pH of 4.

• 14 (1) No person shall sell a cosmetic for use in the area of the eye that contains any coal tar dye,
coal tar dye base or coal tar dye intermediate.

• (2) For the purpose of subsection (1) and section 15.1, “area of the eye” means the area bounded
by the supraorbital and infraorbital ridges and includes the eyebrows, the skin underlying the
eyebrows, the eyelids, the eyelashes, the conjunctival sac of the eye, the eyeball and the soft tissue
that lies below the eye and within the infraorbital ridge 14


15 No manufacturer or importer shall sell a cosmetic that contains (a) chloroform as an ingredient; or

(b) an estrogenic substance.

15.1 No manufacturer or importer shall sell a cosmetic that contains mercury or a salt or derivative
thereof unless

(a) the cosmetic is intended for use in the area of the eye;

(b) the mercury or its salt or derivative thereof is used in the cosmetic as a preservative; and

(c) the manufacturer or importer
• (i) has in his possession evidence demonstrating that the only satisfactory way to maintain the

sterility or stability of the cosmetic is to use mercury or a salt or derivative thereof as a
preservative, and

• (ii) at the Minister’s request, provides the Minister with the evidence described in subparagraph
(i). 15


15.2 No person shall sell a cosmetic described in section 28.2 or 28.3
unless it is packaged in a child-resistant container
16 No person shall sell a cosmetic unless it is labelled in accordance
with these Regulations. 16