1. Suitability and Quality of Packaging Materials for Drugs & Biologicals
Dr. Bhaswat S. Chakraborty
Sr. Vice President, Research & Development,
Cadila Pharmaceuticals Ltd., Ahmedabad
Good packaging system is an integral part of an effective, safe and quality medicine. It is not merely a
good dressing to create an attractive market image of the product. A packaging system or container
closure system is a technical name for all those packaging components that contain, protect and
maintain the quality of such a medicine (drug, biological or vaccine). Such a system includes primary
packaging components and sometimes secondary components as well, when additional protection or
other purposes are to be served. Glass and plastics are often used as the material in the primary
packaging of bottles, ampoules, vials, pre‐filled syringes etc., whereas cardboard paper is extensively
used in the secondary packaging. In addition, a market package contain labeling, dispensing accessories
and wraps, and this entire market package is the one that a retail consumer receives.
This article briefly summarizes the Suitability and Quality Control guidelines for Packaging Materials
mainly based on USFDA suggestions.
Figure 1: Factors governing the suitability and quality control of the container closure system
(also known as packaging system) used in an NDA, ANDA or BLA.
Regulatory agencies would require the sponsor of the New Drug or Biologics application to provide full
description of the container and closure system and its compatibility with the drug and excipients. Each
system must be specific for the drug or biologic for which it has been designed. Figure 1 depicts the
factors governing the suitability and quality control of the packaging system used in an application. The
quality and quantity of information also depend on route of administration of the dosage form and the
likelihood of its interaction with packaging components. For example, information of an inhalation
product packaging has to be more elaborate than that of oral solution or tablet (Figure 2).

2. Suitability of Packaging System for Intended Use
Needless to say, a packaging system must be suitable for its intended use. Suitability, here, has a
specific meaning in that it should adequately protect the dosage form, be compatible with the latter and
Figure 2: Examples of packaging concerns for common classes of drug products (adapted from
US FDA guidance). The higher the concerns and the likelihood of interaction of packaging
material and dosage form, more elaborate information would be required by the regulators.
be composed of materials that are safe for use with the dosage form and the route of administration. In
addition, if it has a performance feature in addition to containing the product, the composite container
closure system must function properly. Detailed description of the tests, methods, acceptance criteria,
reference standards, and validation information for the studies should be provided directly in the
application or indirectly through a DMF.
Protection: Packaging system must provide adequate protection from exposure to light, loss of solvent,
exposure to reactive gases (e.g., oxygen), absorption of water vapor, microbial contamination or any
other contamination. Not all products would be affected by all these factors. Well designed laboratory
studies can determine which factors are actually affecting a particular drug product.
There are standard ways of achieving protection from the factors listed above. For example, protection
from light is achieved by using an opaque or amber‐colored Container. Loss of solvent can be avoided by
sealing the leaks or using a less permeable barrier. Similarly, absorption of water vapor can be stopped
by using proper glass containers with effective sealing. Protection from microbial contamination can be
achieved by maintaining container integrity after the packaging system has been sealed. There are also
innovative and emerging technologies that can be used to give an adequate and measurable protection
by packaging of the drug products.

3. All tests for assuring protection must be well designed and completely validated.
Compatibility: Sometimes a packaging component can interact with the drug product (drug or
excipient). Examples of such interactions include degradation of the active drug induced by a chemical
leaching from the packaging component or reduction in the concentration of the excipients because of
absorption. Changes in drug product pH, discoloration of dosage form or the packaging component
brittleness of the latter due to such interaction constitute some other examples.
Qualification studies on the container closure system can detect some of these interactions. In order to
detect other interactions one must carry out suitable stability indicating assays. Any change that is
indicative of an interaction between the dosage form and packaging component should be investigated
such that its root cause is identified, corrected and documented.
Safety: The materials used in packaging system and its components must be such that they will not
exude or leach any toxic or undesirable substances that will cause an adverse reaction in patients who
are being treated with the drug product. This is especially true for those components which are in direct
contact with the dosage form or may diffuse into the dosage form such as an ink or an adhesive. As
depicted in Figure 2, the safety concerns (because of interaction between dosage form and packaging)
may increase the depending on the route of administration. Therefore, good amount of
experimentations along with knowledge from literature must be used to minimize the safety risks.
For an injection, inhalation, ophthalmic, or transdermal, a comprehensive safety study is appropriate. An
extraction study on the packaging component determining the concentrations of the chemicals leaching
out of the packing component must be followed by a toxicological evaluation of those chemicals. The
toxicological evaluation of the chemicals posing safety risks are based on standard scientific principles
that take in to account a packaging component, the drug product, the route of administration and
chronic or acute exposure. For many injectable and ophthalmic drug products, data from the USP
Biological Reactivity Tests and USP Elastomeric Closures for Injections provide sufficient evidence of
material safety.
In USA, materials used for packaging components in containing many solid and liquid oral products, can
be tested using food additive regulations (21 CFR 174‐186). These regulations include purity criteria and
limitations pertaining to the use of specific materials for packaging foods that may be acceptable for the
evaluation of drug product packaging components.
Performance: A container closure system should be able to function in a manner for which it is intended
to. It does more than simply containing the dosage form. When evaluating its performance, its
functionality and drug delivery — both are considered.
Container closure system functionality may improve patient compliance (e.g., a cap that contains a
counter), minimize waste (e.g., a two‐chamber vial or IV bag) or improve ease of use (e.g., a
Pre‐filled syringe).
Drug delivery is the performance of a packaging system to deliver the dosage form in the amount or at
the rate described in the package insert. A prefilled syringe, a transdermal patch or a metered tube is an
example of such delivery performance.

4. Additional performance of the packaging material may have to withstand the rigors of loading, shipping
and storing.
Quality Control of Packaging Components
Suitability for intended use of the packaging material must be complemented with appropriate use of
quality control measures to assure its standard and consistency in all batches of production of the
dosage form. These will limit the variation in specification of manufacturing procedures and raw
materials for packaging construct. Table 1 summarizes principal physicochemical considerations applied
in the quality control of pharmaceutical packaging systems.
Table 1 : Quality control of packaging components based on physical characterization and chemical
composition
Physical characteristics Chemical composition
Dimensional criteria Change in formulation
Physical parameters for consistent
manufacturing
Change in processing aid
Performance characteristics Change in the manufacturing process
Other parameters Change in supplier of raw materials
Among the physical characteristics, dimensional criteria include control of shape, neck finish, wall
thickness, design tolerances, etc., whereas manufacturing parameters of a packaging component
indicate consistency in unit and weight, etc. Performance characteristics, on the other hand, is
exemplified by metering a valve delivery or ease of a syringe movement. Variations in dimensional
parameter may affect package permeability and drug delivery performance. Variation in physical
manufacturing parameter can affect the quality of a dosage form.
The chemical composition of the material that has been used to construct the packaging can affect
safety, compatibility and performance of the drug product. New or unknown materials can interact with
the drug or excipinets or change the flow properties of the formulation. A composition change may be a
result of a change in formulation, in a processing aid or because of a new supplier of raw materials. The
use of stability indicating assays and stability studies with pre‐defined specifications to preserve
chemical compositions are the key to a successful quality control program. These programs definitely
ensure protection and performance of the packaging system. Except for inhalation products, however,
right now there is no regulation for strict monitoring of packaging system to ensure safety.
In most of the pharmaceutical companies, packaging inspection is part of quality control. These days,
this function is as much automated as possible. However, in the physical and chemical checks, there are
still areas which are best done manually with bare human senses with adequate training.
Conclusion
Modern packaging systems for drug and biological products are well suited for their intended use. They
not only give protection to the contents, they are also reliably safe, compatible with the drug and

5. excipents. Packaging components perform up to the functional standard specified in their intended use
and also deliver the dosage form in the amount or at the rate described in the package insert. Quality
control of the packaging materials including the raw chemicals to construct these materials is carried out
to maintain consistency in both physical characters and chemical composition.