Control of component, containers and closures

Control of components, containers &
closures, production & process control:
packaging &labeling control
ABDUL MUHEEM
M.PHARMA II SEM.
(PHARMACEUTICS)

Control of component, containers
and closures
Subpart E

INTRODUCTION
 A draft of GMP regulations was prepared in 1975
which was implemented in 1988 in the form of
amended Schedule M.
 GMPs form the heart of quality
 GMPs comprises a set of practices that ensures
quality at every level of operation in an industry.
 GMPs provide quality assurances that off-the-
shelf testing can´t.
 GMPs are more immediate and consistent way to
control quality.
4/26/20133

As per FDA, CFR - Code of Federal Regulations
Title 21
 Part 210 :- Current Good Manufacturing Practice in
Manufacturing, Processing, Packing and Holding of Drugs
Part 211: - GMP for Finished Pharmaceuticals
Part 225:- Current GMP for medicated feeds
Part 600: Biologics
Part 820: Medical Devices
4/26/20134

Subparts of Schedule-M
Subpart:
A – Finished Pharmaceuticals:
B – Organization and Personnel
C – Building and Facilities
D – Equipments
E – Control of Components and Drug Product
Container and Closure
F – Production and Process Control
G – Packaging and Labeling Control
H – Holding and Distribution
I – Laboratory Control
J – Records and Report
4/26/20135

Section
 211.80 General requirements
 211.82 Receipt and storage of untested
components, drug product containers, and closures
 211.84 Testing and approval or rejection of
components, drug product containers, and closures
 211.86 Use of approved components, drug product
containers, and closures.
 211.87 Retesting of approved components, drug product
 211.89 Rejected components, drug product
containers, and closures
 Drug product containers and closures

211.80 General requirements.
 (a) There shall be written procedures describing in sufficient detail the
receipt, identification, storage, handling, sampling, testing, and approval
or rejection of components and drug product containers and closures;
such written procedures shall be followed.
 (b) Components and drug product containers and closures shall at all
times be handled and stored in a manner to prevent contamination.
 (c) Bagged or boxed components of drug product containers, or closures
shall be stored off the floor and suitably spaced to permit cleaning and
inspection.
 (d) Each container or grouping of containers for components or drug
product containers, or closures shall be identified with a distinctive code .
This code shall be used in recording the disposition of each lot. Each lot
shall be appropriately identified as to its status

211.82 Receipt and storage of
untested components, drug product
a) Upon receipt and before acceptance, each container or grouping of
containers of components, drug product containers, and closures shall
be examined visually for appropriate labelling as to
contents, container damage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be stored
under quarantine until they have been tested or examined, whichever
is appropriate, and released. Storage within the area shall conform to
the requirements of § 211.80.

211.84 Testing and approval or
rejection of components, drug product
(a) Each lot of components, drug product containers, and closures
shall be withheld from use until the lot has been
sampled, tested, or examined, as appropriate, and released for
use by the quality control unit.
(b) Representative samples of each shipment of each lot shall be
collected for testing or examination. The number of containers to
be sampled, and the amount of material to be taken from each
container, shall be based upon appropriate criteria such as
statistical criteria for component variability, confidence levels, and
degree of precision desired, the past quality history of the
supplier, and the quantity needed for analysis and reserve where
required by § 211.170.

(c) Samples shall be collected in accordance
with the following procedures:
(1) The containers of components selected shall be
cleaned when necessary in a manner to prevent
introduction of contaminants into the component.
(2) The containers shall be opened, sampled, and
resealed in a manner designed to prevent contamination
of their contents and contamination of other
components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques
shall be used when necessary.

(4) If it is necessary to sample a component from the
top, middle, and bottom of its container, such sample
subdivisions shall not be composited for testing.
(5) Sample containers shall be identified so that the following
information can be determined: name of the material
sampled, the lot number, the container from which the
sample was taken, the date on which the sample was
taken, and the name of the person who collected the sample.
(6) Containers from which samples have been taken shall be
marked to show that samples have been removed from them.

(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of each
component of a drug product. Specific identity tests, if they exist, shall be
used.
(2) Each component shall be tested for conformity with all appropriate written
specifications for purity, strength, and quality.
(3) Containers and closures shall be tested for conformity with all appropriate
written specifications.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable
to contamination with filth, insect infestation, or other extraneous adulterant
shall be examined against established specifications for such contamination.

(6) Each lot of a component, drug product container, or closure with
potential for microbiological contamination that is objectionable in
view of its intended use shall be subjected to microbiological tests
before use.
(e) Any lot of components, drug product containers, or closures that
meets the appropriate written specifications of
identity, strength, quality, and purity and related tests under
paragraph (d) of this section may be approved and released for use.
Any lot of such material that does not meet such specifications shall
be rejected.

211.86 Use of approved
components, drug product
Components, drug product containers, and closures
approved for use shall be rotated so that the oldest
approved stock is used first. Deviation from this
requirement is permitted if such deviation is
temporary and appropriate.

211.87 Retesting of approved
 Components, drug product containers, and closures shall be
retested or re-examined, as appropriate, for
identity, strength, quality, and purity and approved or
rejected by the quality control unit in accordance with
§ 211.84 as necessary, e.g., after storage for long periods or
after exposure to air, heat or other conditions that might
adversely affect the component, drug product container, or
closure.

211.89 Rejected
 Rejected components, drug product
containers, and closures shall be identified and
controlled under a quarantine system designed to
prevent their use in manufacturing or processing
operations for which they are unsuitable.

211.94 Drug product
containers and closures
 (a) Drug product containers and closures shall not be
reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the drug beyond the
official or established requirements.
 (b) Container closure systems shall provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product.
 (c) Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to
remove pyrogenic properties to assure that they are suitable for their
intended use. Such depyrogenation processes shall be validated.
 (d) Standards or specifications, methods of testing, and, where
indicated, methods of cleaning, sterilizing, and processing to remove
pyrogenic properties shall be written and followed for drug product
containers and closures.

1. Assure that your company’s products are meeting the needs of
customers with regard to quality and that company suppliers are
meeting internal company requirements.
2. Validate and/or map the current processes for the selected
products.
3. Evaluate whether the current product and process controls that are
in place are able to meet these needs.
4. Identify optimized or new “Critical to Quality – Critical to
Customer” requirements for the “vital few” needs and assure that
an effective “process control system control plan” is in place for
the selected products and sub-components to assure customer and
company needs are satisfied.
5. Create small process control teams that will optimize existing or
create Product and Process Control Systems for the selected
products.
6. Schedule time over the next few weeks to begin the process of
improving the process controls and metrics defined in the control
systems.
Purpose

Steps involved in process control
1. Written procedures, deviations
2. Charge-in of components
3. Calculation of yield
4. Equipment identification
5. Sampling and testing of in-process material and
drug products
6. Time limitation on production
7. Control of microbiological contamination
8. Reprocessing

Written procedures & deviations
 Written procedures for production and process control designed to
assure that the drug products have the identity, strength, quality, and
purity they purport or are represented to possess.
These written procedures, including any changes, shall be
drafted, reviewed, and approved by the appropriate organizational
units and reviewed and approved by the quality control unit.
Written production and process control procedures shall be
followed in the execution of the various production and process
control functions and shall be documented at the time of
performance. Any deviation from the written procedures shall be
recorded and justified.

Charge-in of components.
Written production and control procedures shall include the
following:
(a) The batch shall be formulated with the intent to provide not less
than 100 percent of the labeled or established amount of active
ingredient.
(b) Components for drug product manufacturing shall be
weighed, measured, or subdivided as appropriate.
If a component is removed from the original container to another, the
new container shall be identified with the following information:

(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components shall
be adequately supervised. Each container of component dispensed to
manufacturing shall be examined by a second person to assure that:
(1) Component was released by the quality control unit
(2) Weight or measure is correct as stated in the batch production records

(3) The containers are properly identified.
If the weighing, measuring, or subdividing operations are performed
by automated equipment, only one person is needed to assure
paragraphs (c)(1), (c)(2), and (c)(3) of this section.
(d) Each component shall either be added to the batch by one person
and verified by a second person or, if the components are added by
automated equipment, only verified by one person.

Calculation of yield
Actual yields and percentages of theoretical yield shall be
determined at the conclusion of each appropriate phase of
manufacturing, processing, packaging, or holding of the drug
product.
Such calculations shall either be performed by one person and
independently verified by a second person, or, if the yield is
calculated by automated equipment under 211.68, be independently
verified by one person.

Equipment Identification
(a) All compounding and storage containers, processing lines, and
major equipment used during the production of a batch of a drug
product shall be properly identified at all times to indicate their
contents and, when necessary, the phase of processing of the
batch
(b) Major equipment shall be identified by a distinctive identification
number or code that shall be recorded in the batch production record
to show the specific equipment used in the manufacture of each
batch of a drug product.
In cases where only one of a particular type of equipment exists in a
manufacturing facility, the name of the equipment may be used in
lieu of a distinctive identification number or code.

Sampling and testing of in-process materials
and drug products
 To assure batch uniformity and integrity of drug
products, written procedures shall be established and followed that
describes the in-process controls, and test, or examination to be
conducted on appropriate sample of in-process materials of each
batch.(e.g. Tablet wt. variation, Dist. time, Disso. time)
 Valid in-process specifications for such characteristic should be
consistent with drug product final specifications and shall be derived
from previous acceptable estimates.
 In-process material shall be tested for
identity, strength, quality, and purity as appropriate and approved
or rejected by the QC unit, during the production process.

Time limitations on production.
When appropriate, time limits for the completion of each phase of
production shall be established to assure the quality of the drug
product
 Deviation from established time limits may be acceptable if such
deviation does not compromise the quality of the drug product.
Such deviation shall be justified and documented.

Control of microbiological contamination
Appropriate written procedures, designed to prevent
objectionable microorganisms in drug products not required to
be sterile, shall be established and followed.
Microbial monitoring of potentially susceptible raw materials
Equipment sanitation procedures which have been proven
effective
Processing conditions which minimize the potential for
microbial growth
Environmental control including covers over equipment;
laminar flow at susceptible points, wearing gloves, mask
Formulations to include preservatives.

Reprocessing
(a) Written procedures shall be established and followed
prescribing a system for reprocessing batches that do not
conform to standards or specifications and the steps to be taken
to insure that the reprocessed batches will conform with all
established standards, specifications, and characteristics.
(b) Reprocessing shall not be performed without the review and
approval of the quality control unit.

Packaging & Labeling
Control
31

INTRODUCTION TO PHARMACEUTICAL
PACKAGING
Packaging is the science, art and technology of enclosing or protecting products
for distribution, storage, sale, and use. Packaging also refers to the process of
design, evaluation, and production of packages.
Packaging contains, protects, preserves, transports, informs, and sells. It is fully
integrated into government, business, institutional, industry, and personal use.
1.1 The Pack
A simple definition of a pack is:
A pack is the economical means of providing for a product
• Presentation
• Protection
• Identification/information
• Convenience/containment/compliance
Until such time as the product is used or administered, paying due attention to any
relevant environmental issues.
32

•The term ‘pack’ in the above covers all the components
involved, i.e. the primary or immediate pack, which
consists of those materials in direct contact with the
product.
•The secondary pack and sometimes tertiary
components enable the product to be stored, transported
and displayed, and possibly assist use.
•Tertiary components may include ancillary components
e.g. leaflets or inserts, separate dispensing spoons and
measures.
33

Qualities of the Package
For any packaging material basic 5 qualities are required.
1)Protection
Must protect against all adverse external influences that may affect
quality, such as light, moisture, oxygen, mechanical damage.
Some aspects of protection are superficial, such as the wrapping of an
outer carton in cellulose film to avoid dust, but the protection given to the
product by the primary package is very important.
2) Identification
The package must also give clear identification of the product at all stages
and, again, the life of the patient may depend upon rapid and correct
identification in emergencies.
Often, the package is required to identify the manufacturer to the user by a
characteristic house style.34

3}Presentation:-
Good presentation enhances the product and attracts the consumer during
storage or display. In addition, the public can judge the product only by the
appearance of the package, so that a dignified and professional presentation
will give confidence to the user.
4}Convenience:-
The form of package should be such that it offers convenience at all stages of
its life history and the design of the package should be convenient for
manufacturer, for transport and storage and for the use by consumer.
5}Economic:-
The economics of packaging are considerable practical importance; the
package cost should be minimal, provided the previous qualities are not
prejudiced. In particular, care should be taken to ensure that protection is not
sacrificed simply to reduce package costs.
35

Package Material Properties:-
•Mechanical properties
The materials must give the container sufficient mechanical
strength to withstand handling empty, when filling, and when
closing (all these are often performed mechanically); processing
(labeling, sterilization, etc.), transports, storage and supply to,
and use by, the consumer.
Typical of the care in design needed in this respect are glass
containers.
36

•Physical properties:-
The container must be able to withstand heat if the processing
includes the sterilization.
The surface must be capable of clear labeling, often difficult, for
e.g., with plastics.
The material must protect from light, if necessary it must be ultra
violet absorbent.
The container must not attract substances from product; e.g.,
absorption of water from creams into cardboard boxes.
37

•Chemical properties:-
The container and closure should not react together, either
alone or in the presence of the product.
The product should not react with the containers or closures,
as might happen if alkaline substances are packed in
aluminum containers.
Substances must not be abstracted from the product, such as
the loss of bactericides from injection solutions to rubber.
The containers or closures must not yield substances to the
product; for example, alkali from glass or plasticizer from
plastics.
38

•Biological properties :-
The materials of the containers must be able to protect the attack by the
insect if this hazard is likely to be encountered.
The package should not support the mould growth.
39

Packaging Materials
•Metals
Metal containers are used mainly for dry products, due to the effect of trace
metal contamination introduced by the corrosion, especially of iron.
Aluminum containers and collapsible tubes for creams and ointments.
Metal foils, especially aluminum are used for sachets and unit pack of tablets.
•Plastics
Coming into increasing use are Phenol, urea, melamine- formamide resin as
screw closure.
Polystyrene tubes for tablets
Polyethylene is widely used for flexible containers, closures, bags, etc.
Polypropylene is similar to polyethylene but it has greater transparency and
better heat resistance. It is also more resistant to attack by solvent, but more
expensive than polyethylene.
Cellulose acetate is used as films for unit packs of tablets in the same way as
foils, but it has lower strength and moisture resistance.
40

•Paper and board
Papers and boards have a variety or uses for external packages, but used for
the primary packs is limited; usually impregnated, for e.g. with wax or plastics.
•Glass
Type I glass (commonly known as neutral glass) offers a high hydrolytic
resistance due to chemical composition of the glass.
Type II glass has a high hydrolytic resistance due to an appropriate surface
treatment. Both types of glass may be used for different types of injectable
preparations.
Type III glass offers only a moderate hydrolytic resistance and should be used
only for non-aqueous liquid preparations or for powders for injection or for
injectable preparation where adequate suitability tests have indicated that this
type of glass is satisfactory or for preparations not for parenteral use.
Containers of Type II or Type III glass should be used once only.
Glass may have additives to absorb light particularly ultraviolet.
•Rubber
It is needed in a specialized form for closure for injection containers.41

The Purposes of Packaging:-
Packaging and package labeling have several objectives.
•Physical protection
The objects enclosed in the package may require protection from, among
other things, shock, vibration, compression, temperature, etc.
•Barrier protection
A barrier from oxygen, water vapor, dust, etc., is often required.
Keeping the contents clean, fresh, sterile and safe for the intended shelf life
is a primary function.
•Containment or agglomeration
Small objects are typically grouped together in one package for reasons of
efficiency. For example, a single strip of 10 tablets requires less physical
handling than 10 tablets.
42

•Information transmission:-
Packages and labels communicate how to use, transport,
recycle, or dispose of the package or product.
•Marketing
The packaging and labels can be used by marketers to
encourage potential buyers to purchase the product.
•Security
Reducing the security risks of shipment.
Packages can be made with improved tamper resistance.
•Convenience
Packages can have features which add convenience in
distribution, handling, stacking, display, sale, opening,
reclosing, use, and reuse.43

Packaging instructions :-
Following instruction:
(a) the name of the product;
(b) a description of its pharmaceutical form, strength and, ,
method of application;
(c) the pack size , weight or volume of the product in the ﬁnal
container;
(d) a complete list of all the packaging materials required for a
standard batch size, including quantities, sizes and types, with
the reference number relating to the speciﬁcations for each
packaging material;
44

(e) where the batch number and expiry date of the
product have been marked;
(f) special precautions .
(g) a description of the packaging operation,
including any signiﬁcant subsidiary operations, and
equipment to be used;
(h) details of in-process controls with instructions
for sampling and acceptance limits.
45

Labelling:-
Labels applied to containers, equipment or premises should be clear. It is often
helpful in addition to the wording on the labels to use colours to indicate status (e.g.
quarantined, accepted, rejected, clean).
(a) the name of the drug product;
(b) a list of the active ingredients , showing the amount of each present and a
statement of the net contents (e.g. number of dosage units, weight, volume);
•e.g:pcm 500 mg
(c) the batch number assigned by the manufacturer;
(d) the expiry date
(e) special storage condition.
(f) directions for use, and warnings and precautions that may be necessary;
(g) the name and address of the manufacturer or the company .
47

Labeling issuance:-
a. Strict control shall be exercised over labelling issued for use in drug
product labelling Operations.
b. All excess labeling bearing control numbers shall be destroyed.
c. Procedures in sufficient detail shall be employed for the issuance of
labeling.
III. Packaging and labeling operations:
a. Identification need not be applied to each individual
container.
b. Identification of the drug product with a control number that
permit history of Manufacture.
49

c. Inspection of the packaging and labeling facilities immediately
before use to assure that all drug products have been removed from
previous operation.
Tamper-evident packaging
requirements for OTC human drug
products:
a. A tamper-evident package may involve an immediate container and
closure system to Provide a visual indication of package integrity.
b. In addition to the tamper-evident packaging feature hard gelatin
capsule covered by this section must be sealed using an acceptable
tamper-evident technology.
Expiration dating:
a. Expiration dates shall appear on labeling in accordance with the
requirements.
b. Homeopathic drug products shall be exempt from the requirements.
50

Line clearance:-
The term line clearance is used for the documented act of conducting any necessary
removal of products and materials from a manufacturing line to prepare the line for
the next production(packaging).
A line clearance procedure is having three stages
Clearing:-
Remove the previous product related items from the area/line i.e. pre printed
ampoules , plugs , left over solution/material , product , labels , printed cartons.
Cleaning:-
Cleaning to be carried out only after clearing of previous products.
Clean the as per current SOP.
Checking:-
Checking to be carried out only after clearing and cleaning of previous products.
51

Reconciliation of labels:
It is a method and means for reconciliation between faulty
labels identified during a labeling operation and removed
from the operation.
It is plays an imp role during label issuance. It is an
important to reconcile all the packaging material;
especially the over printed packing materials like
labels,cartons and wrappers because it leads to misuse and
product mix-ups if not accounted.
52

Procedure:-
•On the completion of packing of particular batch determine the
•Quality of labels used
•Quality of labels rejected.
• Labels used for quality control for testing, for control samples.
•Quality used for relabeling and balance labels.
This totally reconcile quantity is compared with the intended quantity.
Note the variance and destroy all the balance and rejected labels under
proper supervision.
B) Boxes, cartons, wrappers
At the end of packing operation, determine the number of boxes,
cartons, wrappers used. To this add the quality taken by the quality
control for checking, for control samples, rejection online due to defects
and the balance quantity of the packaging.
Calculate and note the variance, the rejected and balance packing
material should be destroyed Under proper super vision.
53

References
• Good manufacturing practices for pharmaceuticals ,
Sidney H. willig & James R. stoker ,fifth edition,page no:139-172
 http://www.ecfr.gov/cgi-bin/text-
idx?c=ecfr;rgn=div6;idno=21;sid=5dd76aad30ac0788c6
a7386f110d91ec;view=text;cc=ecfr;node=21%3A4.0.1.
1.11.5#21:4.0.1.1.11.5.1.1
 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/
CFRSearch.cfm?CFRPart=211&showFR=1&subpartNode=
21:4.0.1.1.11.5
 http://www.fda.gov/Drugs/GuidanceComplianceRegulato
ryInformation/Guidances/ucm124780.htm#2
 http://openlearningworld.com/Regulatory_Reqs_for_Pha
rmaceutical_Products/Regulatory_Reqs_for_Pharmaceuti
cal_Products_Course_Files_a0a1.html

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