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

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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

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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

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