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Control of components, containers &closures, production
& process control:packaging &labeling controlABDUL
MUHEEMM.PHARMA II SEM.(PHARMACEUTICS)
Control of component, containersand closuresSubpart E
INTRODUCTION A draft of GMP regulations was prepared in
1975which was implemented in 1988 in the form ofamended Schedule M.
GMPs form the heart of quality GMPs comprises a set of practices
that ensuresquality at every level of operation in an industry.
GMPs provide quality assurances that off-the-shelf testing cant.
GMPs are more immediate and consistent way tocontrol
quality.4/26/20133
As per FDA, CFR - Code of Federal RegulationsTitle 21 Part 210
:- Current Good Manufacturing Practice inManufacturing, Processing,
Packing and Holding of DrugsPart 211: - GMP for Finished
PharmaceuticalsPart 225:- Current GMP for medicated feedsPart 600:
BiologicsPart 820: Medical Devices4/26/20134
Subparts of Schedule-MSubpart:A Finished Pharmaceuticals:B
Organization and PersonnelC Building and FacilitiesD EquipmentsE
Control of Components and Drug ProductContainer and ClosureF
Production and Process ControlG Packaging and Labeling ControlH
Holding and DistributionI Laboratory ControlJ Records and
Report4/26/20135
Section 211.80 General requirements 211.82 Receipt and storage
of untestedcomponents, drug product containers, and closures 211.84
Testing and approval or rejection ofcomponents, drug product
containers, and closures 211.86 Use of approved components, drug
productcontainers, and closures. 211.87 Retesting of approved
components, drug productcontainers, and closures. 211.89 Rejected
components, drug productcontainers, and closures Drug product
containers and closures
211.80 General requirements. (a) There shall be written
procedures describing in sufficient detail thereceipt,
identification, storage, handling, sampling, testing, and
approvalor 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 alltimes be
handled and stored in a manner to prevent contamination. (c) Bagged
or boxed components of drug product containers, or closuresshall be
stored off the floor and suitably spaced to permit cleaning
andinspection. (d) Each container or grouping of containers for
components or drugproduct containers, or closures shall be
identified with a distinctive code .This code shall be used in
recording the disposition of each lot. Each lotshall be
appropriately identified as to its status
211.82 Receipt and storage ofuntested components, drug
productcontainers, and closuresa) Upon receipt and before
acceptance, each container or grouping ofcontainers of components,
drug product containers, and closures shallbe examined visually for
appropriate labelling as tocontents, container damage or broken
seals, and contamination.(b) Components, drug product containers,
and closures shall be storedunder quarantine until they have been
tested or examined, whicheveris appropriate, and released. Storage
within the area shall conform tothe requirements of 211.80.
211.84 Testing and approval orrejection of components, drug
productcontainers, and closures(a) Each lot of components, drug
product containers, and closuresshall be withheld from use until
the lot has beensampled, tested, or examined, as appropriate, and
released foruse by the quality control unit.(b) Representative
samples of each shipment of each lot shall becollected for testing
or examination. The number of containers tobe sampled, and the
amount of material to be taken from eachcontainer, shall be based
upon appropriate criteria such asstatistical criteria for component
variability, confidence levels, anddegree of precision desired, the
past quality history of thesupplier, and the quantity needed for
analysis and reserve whererequired by 211.170.
(c) Samples shall be collected in accordancewith the following
procedures:(1) The containers of components selected shall
becleaned when necessary in a manner to preventintroduction of
contaminants into the component.(2) The containers shall be opened,
sampled, andresealed in a manner designed to prevent
contaminationof their contents and contamination of
othercomponents, drug product containers, or closures.(3) Sterile
equipment and aseptic sampling techniquesshall be used when
necessary.
(4) If it is necessary to sample a component from thetop,
middle, and bottom of its container, such samplesubdivisions shall
not be composited for testing.(5) Sample containers shall be
identified so that the followinginformation can be determined: name
of the materialsampled, the lot number, the container from which
thesample was taken, the date on which the sample wastaken, and the
name of the person who collected the sample.(6) Containers from
which samples have been taken shall bemarked 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
eachcomponent of a drug product. Specific identity tests, if they
exist, shall beused.(2) Each component shall be tested for
conformity with all appropriate writtenspecifications for purity,
strength, and quality.(3) Containers and closures shall be tested
for conformity with all appropriatewritten specifications.(4) When
appropriate, components shall be microscopically examined.(5) Each
lot of a component, drug product container, or closure that is
liableto contamination with filth, insect infestation, or other
extraneous adulterantshall be examined against established
specifications for such contamination.
(6) Each lot of a component, drug product container, or closure
withpotential for microbiological contamination that is
objectionable inview of its intended use shall be subjected to
microbiological testsbefore use.(e) Any lot of components, drug
product containers, or closures thatmeets the appropriate written
specifications ofidentity, strength, quality, and purity and
related tests underparagraph (d) of this section may be approved
and released for use.Any lot of such material that does not meet
such specifications shallbe rejected.
211.86 Use of approvedcomponents, drug productcontainers, and
closures.Components, drug product containers, and closuresapproved
for use shall be rotated so that the oldestapproved stock is used
first. Deviation from thisrequirement is permitted if such
deviation istemporary and appropriate.
211.87 Retesting of approvedcomponents, drug productcontainers,
and closures. Components, drug product containers, and closures
shall beretested or re-examined, as appropriate, foridentity,
strength, quality, and purity and approved orrejected by the
quality control unit in accordance with 211.84 as necessary, e.g.,
after storage for long periods orafter exposure to air, heat or
other conditions that mightadversely affect the component, drug
product container, orclosure.
211.89 Rejectedcomponents, drug productcontainers, and closures
Rejected components, drug productcontainers, and closures shall be
identified andcontrolled under a quarantine system designed
toprevent their use in manufacturing or processingoperations for
which they are unsuitable.
211.94 Drug productcontainers and closures (a) Drug product
containers and closures shall not bereactive, additive, or
absorptive so as to alter thesafety, identity, strength, quality,
or purity of the drug beyond theofficial or established
requirements. (b) Container closure systems shall provide adequate
protectionagainst foreseeable external factors in storage and use
that can causedeterioration or contamination of the drug product.
(c) Drug product containers and closures shall be clean and,
whereindicated by the nature of the drug, sterilized and processed
toremove pyrogenic properties to assure that they are suitable for
theirintended use. Such depyrogenation processes shall be
validated. (d) Standards or specifications, methods of testing,
and, whereindicated, methods of cleaning, sterilizing, and
processing to removepyrogenic properties shall be written and
followed for drug productcontainers and closures.
PRODUCTION & PROCESSCONTROL
1. Assure that your companys products are meeting the needs
ofcustomers with regard to quality and that company suppliers
aremeeting internal company requirements.2. Validate and/or map the
current processes for the selectedproducts.3. Evaluate whether the
current product and process controls that arein place are able to
meet these needs.4. Identify optimized or new Critical to Quality
Critical toCustomer requirements for the vital few needs and assure
thatan effective process control system control plan is in place
forthe selected products and sub-components to assure customer
andcompany needs are satisfied.5. Create small process control
teams that will optimize existing orcreate Product and Process
Control Systems for the selectedproducts.6. Schedule time over the
next few weeks to begin the process ofimproving the process
controls and metrics defined in the controlsystems.Purpose
Steps involved in process control1. Written procedures,
deviations2. Charge-in of components3. Calculation of yield4.
Equipment identification5. Sampling and testing of in-process
material anddrug products6. Time limitation on production7. Control
of microbiological contamination8. Reprocessing
Written procedures & deviations Written procedures for
production and process control designed toassure that the drug
products have the identity, strength, quality, andpurity they
purport or are represented to possess.These written procedures,
including any changes, shall bedrafted, reviewed, and approved by
the appropriate organizationalunits and reviewed and approved by
the quality control unit.Written production and process control
procedures shall befollowed in the execution of the various
production and processcontrol functions and shall be documented at
the time ofperformance. Any deviation from the written procedures
shall berecorded and justified.
Charge-in of components.Written production and control
procedures shall include thefollowing:(a) The batch shall be
formulated with the intent to provide not lessthan 100 percent of
the labeled or established amount of activeingredient.(b)
Components for drug product manufacturing shall beweighed,
measured, or subdivided as appropriate.If a component is removed
from the original container to another, thenew 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 productname, strength, and
lot number.(c) Weighing, measuring, or subdividing operations for
components shallbe adequately supervised. Each container of
component dispensed tomanufacturing 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 performedby automated
equipment, only one person is needed to assureparagraphs (c)(1),
(c)(2), and (c)(3) of this section.(d) Each component shall either
be added to the batch by one personand verified by a second person
or, if the components are added byautomated equipment, only
verified by one person.
Calculation of yieldActual yields and percentages of
theoretical yield shall bedetermined at the conclusion of each
appropriate phase ofmanufacturing, processing, packaging, or
holding of the drugproduct.Such calculations shall either be
performed by one person andindependently verified by a second
person, or, if the yield iscalculated by automated equipment under
211.68, be independentlyverified by one person.
Equipment Identification(a) All compounding and storage
containers, processing lines, andmajor equipment used during the
production of a batch of a drugproduct shall be properly identified
at all times to indicate theircontents and, when necessary, the
phase of processing of thebatch(b) Major equipment shall be
identified by a distinctive identificationnumber or code that shall
be recorded in the batch production recordto show the specific
equipment used in the manufacture of eachbatch of a drug product.In
cases where only one of a particular type of equipment exists in
amanufacturing facility, the name of the equipment may be used
inlieu of a distinctive identification number or code.
Sampling and testing of in-process materialsand drug products
To assure batch uniformity and integrity of drugproducts, written
procedures shall be established and followed thatdescribes the
in-process controls, and test, or examination to beconducted on
appropriate sample of in-process materials of eachbatch.(e.g.
Tablet wt. variation, Dist. time, Disso. time) Valid in-process
specifications for such characteristic should beconsistent with
drug product final specifications and shall be derivedfrom previous
acceptable estimates. In-process material shall be tested
foridentity, strength, quality, and purity as appropriate and
approvedor rejected by the QC unit, during the production
process.
Time limitations on production.When appropriate, time limits
for the completion of each phase ofproduction shall be established
to assure the quality of the drugproduct Deviation from established
time limits may be acceptable if suchdeviation does not compromise
the quality of the drug product.Such deviation shall be justified
and documented.
Control of microbiological contaminationAppropriate written
procedures, designed to preventobjectionable microorganisms in drug
products not required tobe sterile, shall be established and
followed.Microbial monitoring of potentially susceptible raw
materialsEquipment sanitation procedures which have been
proveneffectiveProcessing conditions which minimize the potential
formicrobial growthEnvironmental control including covers over
equipment;laminar flow at susceptible points, wearing gloves,
maskFormulations to include preservatives.
Reprocessing(a) Written procedures shall be established and
followedprescribing a system for reprocessing batches that do
notconform to standards or specifications and the steps to be
takento insure that the reprocessed batches will conform with
allestablished standards, specifications, and characteristics.(b)
Reprocessing shall not be performed without the review andapproval
of the quality control unit.
Packaging & LabelingControl31
INTRODUCTION TO PHARMACEUTICALPACKAGINGPackaging is the
science, art and technology of enclosing or protecting productsfor
distribution, storage, sale, and use. Packaging also refers to the
process ofdesign, evaluation, and production of packages.Packaging
contains, protects, preserves, transports, informs, and sells. It
is fullyintegrated into government, business, institutional,
industry, and personal use.1.1 The PackA simple definition of a
pack is:A pack is the economical means of providing for a product
Presentation Protection Identification/information
Convenience/containment/complianceUntil such time as the product is
used or administered, paying due attention to anyrelevant
environmental issues.32
The term pack in the above covers all the componentsinvolved,
i.e. the primary or immediate pack, whichconsists of those
materials in direct contact with theproduct.The secondary pack and
sometimes tertiarycomponents enable the product to be stored,
transportedand displayed, and possibly assist use.Tertiary
components may include ancillary componentse.g. leaflets or
inserts, separate dispensing spoons andmeasures.33
Qualities of the PackageFor any packaging material basic 5
qualities are required.1)ProtectionMust protect against all adverse
external influences that may affectquality, such as light,
moisture, oxygen, mechanical damage.Some aspects of protection are
superficial, such as the wrapping of anouter carton in cellulose
film to avoid dust, but the protection given to theproduct by the
primary package is very important.2) IdentificationThe package must
also give clear identification of the product at all stagesand,
again, the life of the patient may depend upon rapid and
correctidentification in emergencies.Often, the package is required
to identify the manufacturer to the user by acharacteristic house
style.34
3}Presentation:-Good presentation enhances the product and
attracts the consumer duringstorage or display. In addition, the
public can judge the product only by theappearance of the package,
so that a dignified and professional presentationwill give
confidence to the user.4}Convenience:-The form of package should be
such that it offers convenience at all stages ofits life history
and the design of the package should be convenient formanufacturer,
for transport and storage and for the use by
consumer.5}Economic:-The economics of packaging are considerable
practical importance; thepackage cost should be minimal, provided
the previous qualities are notprejudiced. In particular, care
should be taken to ensure that protection is notsacrificed simply
to reduce package costs.35
Package Material Properties:-Mechanical propertiesThe materials
must give the container sufficient mechanicalstrength to withstand
handling empty, when filling, and whenclosing (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
glasscontainers.36
Physical properties:-The container must be able to withstand
heat if the processingincludes the sterilization.The surface must
be capable of clear labeling, often difficult, fore.g., with
plastics.The material must protect from light, if necessary it must
be ultraviolet 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, eitheralone 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 inaluminum containers.Substances
must not be abstracted from the product, such asthe loss of
bactericides from injection solutions to rubber.The containers or
closures must not yield substances to theproduct; for example,
alkali from glass or plasticizer fromplastics.38
Biological properties :-The materials of the containers must be
able to protect the attack by theinsect if this hazard is likely to
be encountered.The package should not support the mould
growth.39
Packaging MaterialsMetalsMetal containers are used mainly for
dry products, due to the effect of tracemetal 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.PlasticsComing into increasing use are Phenol, urea,
melamine- formamide resin asscrew closure.Polystyrene tubes for
tabletsPolyethylene is widely used for flexible containers,
closures, bags, etc.Polypropylene is similar to polyethylene but it
has greater transparency andbetter heat resistance. It is also more
resistant to attack by solvent, but moreexpensive than
polyethylene.Cellulose acetate is used as films for unit packs of
tablets in the same way asfoils, but it has lower strength and
moisture resistance.40
Paper and boardPapers and boards have a variety or uses for
external packages, but used forthe primary packs is limited;
usually impregnated, for e.g. with wax or plastics.GlassType I
glass (commonly known as neutral glass) offers a high
hydrolyticresistance due to chemical composition of the glass.Type
II glass has a high hydrolytic resistance due to an appropriate
surfacetreatment. Both types of glass may be used for different
types of injectablepreparations.Type III glass offers only a
moderate hydrolytic resistance and should be usedonly for
non-aqueous liquid preparations or for powders for injection or
forinjectable preparation where adequate suitability tests have
indicated that thistype 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.RubberIt is needed in a
specialized form for closure for injection containers.41
The Purposes of Packaging:-Packaging and package labeling have
several objectives.Physical protectionThe objects enclosed in the
package may require protection from, amongother things, shock,
vibration, compression, temperature, etc.Barrier protectionA
barrier from oxygen, water vapor, dust, etc., is often
required.Keeping the contents clean, fresh, sterile and safe for
the intended shelf lifeis a primary function.Containment or
agglomerationSmall objects are typically grouped together in one
package for reasons ofefficiency. For example, a single strip of 10
tablets requires less physicalhandling than 10 tablets.42
Information transmission:-Packages and labels communicate how
to use, transport,recycle, or dispose of the package or
product.MarketingThe packaging and labels can be used by marketers
toencourage potential buyers to purchase the
product.SecurityReducing the security risks of shipment.Packages
can be made with improved tamper resistance.ConveniencePackages can
have features which add convenience indistribution, 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 nalcontainer;(d) a complete list of all the
packaging materials required for astandard batch size, including
quantities, sizes and types, withthe reference number relating to
the specications for eachpackaging material;44
(e) where the batch number and expiry date of theproduct have
been marked;(f) special precautions .(g) a description of the
packaging operation,including any signicant subsidiary operations,
andequipment to be used;(h) details of in-process controls with
instructionsfor sampling and acceptance limits.45
46
Labelling:-Labels applied to containers, equipment or premises
should be clear. It is oftenhelpful 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 astatement 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
48
Labeling issuance:-a. Strict control shall be exercised over
labelling issued for use in drugproduct labelling Operations.b. All
excess labeling bearing control numbers shall be destroyed.c.
Procedures in sufficient detail shall be employed for the issuance
oflabeling.III. Packaging and labeling operations:a. Identification
need not be applied to each individualcontainer.b. Identification
of the drug product with a control number thatpermit history of
Manufacture.49
c. Inspection of the packaging and labeling facilities
immediatelybefore use to assure that all drug products have been
removed fromprevious operation.Tamper-evident packagingrequirements
for OTC human drugproducts:a. A tamper-evident package may involve
an immediate container andclosure system to Provide a visual
indication of package integrity.b. In addition to the
tamper-evident packaging feature hard gelatincapsule covered by
this section must be sealed using an acceptabletamper-evident
technology.Expiration dating:a. Expiration dates shall appear on
labeling in accordance with therequirements.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 necessaryremoval of products and
materials from a manufacturing line to prepare the line forthe next
production(packaging).A line clearance procedure is having three
stagesClearing:-Remove the previous product related items from the
area/line i.e. pre printedampoules , 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 faultylabels identified during a labeling
operation and removedfrom the operation.It is plays an imp role
during label issuance. It is animportant to reconcile all the
packaging material;especially the over printed packing materials
likelabels,cartons and wrappers because it leads to misuse
andproduct mix-ups if not accounted.52
Procedure:-On the completion of packing of particular batch
determine theQuality of labels usedQuality 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
underproper supervision.B) Boxes, cartons, wrappersAt the end of
packing operation, determine the number of boxes,cartons, wrappers
used. To this add the quality taken by the qualitycontrol for
checking, for control samples, rejection online due to defectsand
the balance quantity of the packaging.Calculate and note the
variance, the rejected and balance packingmaterial 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=5dd76aad30ac0788c6a7386f110d91ec;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/GuidanceComplianceRegulatoryInformation/Guidances/ucm124780.htm#2
http://openlearningworld.com/Regulatory_Reqs_for_Pharmaceutical_Products/Regulatory_Reqs_for_Pharmaceutical_Products_Course_Files_a0a1.html