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-theshelf testing cant. GMPs are more immediate and consistent way to control quality.
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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
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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
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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 containers, and closures.

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 containers, and closures
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 containers, and closures
(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 containers, and closures.

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.

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 components, drug product containers, and closures

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.

PRODUCTION & PROCESS CONTROL

Purpose
1. Assure that your companys 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.

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

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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 32such time as the product is used or administered, paying due attention to any relevant environmental issues.

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.
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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 34 characteristic house style.

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 35 prejudiced. In particular, care should be taken to ensure that protection is not sacrificed simply to reduce package costs.

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.

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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.
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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.
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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.

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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 40 acetate is used as films for unit packs of tablets in the same way as foils, but it has lower strength and moisture resistance.

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 42 efficiency. For example, a single strip of 10 tablets requires less physical handling than 10 tablets.

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, 43 reclosing, use, and reuse.

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 nal 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 specications for each 44 packaging material;

(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 signicant subsidiary operations, and equipment to be used;
(h) details of in-process controls with instructions for sampling and acceptance limits.
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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) (b) the name of the drug product; 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 the batch number assigned by the manufacturer; the expiry date special storage condition.

(c) (d) (e)

(f)
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directions for use, and warnings and precautions that may be necessary;
the name and address of the manufacturer or the company .

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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 49 permit history of Manufacture.

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 requirements for products:

OTC

packaging human drug

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.
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b. Homeopathic drug products shall be exempt from the requirements.

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.
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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.

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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 53 material should be destroyed Under proper super vision.

References
Good manufacturing practices for pharmaceuticals , Sidney H. willig & James R. stoker ,fifth edition,page no:139-172 http://www.ecfr.gov/cgi-bin/textidx?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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Thanks for yours attention