PRODUCTION

PRINCIPLE

Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practices in order to provide assurance of consistently yielding pharmaceutical products which conform to the requisite quality and be in accordance with the relevant manufacturing and marketing authorizations.

GENERAL

Production should be performed and supervised by competent people.

All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.

All incoming materials should be checked to ensure that the consignment corresponds to the order. Container should be cleaned where necessary and labelled with the prescribed data.

Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department.

Incoming materials and finished product should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution.

Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.

All materials and products should be stored under the appropriate conditions established by the manufacturer and in anorderly fashioned to permit batch segregation and stock rotation.

Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.

At every stage of processing, products and materials should be protected from microbial and other contamination.

When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials.

At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production.

Labels applied to containers, equipment or premises should be clear, unambiguous and in the company's agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean, etc).

Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.

Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by the head of Quality Management (Quality Assurance) with the involvement of the Quality Control Department when appropriate.

Access to production premises should be restricted to authorised personnel.

Normally, the production of non-pharmaceutical products should be avoided in areas and with the equipment destined for the production of pharmaceutical products.

STARTING MATERIALS

Starting materials should only be purchased from approved suppliers named in the relevant specification.

All incoming, outgoing and remaining materials should be recorded. The record should contain information on supplies, batch or lot number, date of receipt or issuance, date of release and date of expiry if any.

Before release for use, each starting material employed should be in compliance with its specification and labelled with the name designated in the specification. Unauthorized abbreviations, codes or names should not be used.

Each delivery or batch of starting materials should be assigned a reference number which will identify the delivery or batch throughout storage and processing. This number should appear on the labels of the containers and permit access to records which will enable full details of the delivery or batch to be checked.

Different batches within one delivery should be regarded as separate batches for sampling, testing and release purposes.

Each delivery should be visually checked on receipt for general condition, integrity of container(s) and seal, spillage and possible deterioration, and for correspondence between the delivery note and the supplier’s labels and be sampled by personnel and methods approved by the head of Quality Control.

Bulk containers from which sample have been taken should be identified.

The sample should be tested for compliance with the starting material specifications. In certain circumstances, partial or entire compliance with specifications may be demonstrated by the possession of a certificate of analysis supported by first-hand assurance of identity.

Steps should be taken to provide assurance that all containers in a delivery contain the correct starting material, and to safeguard against mislabelling of the containers by the supplier.

Deliveries of starting materials should be held in quarantine until approved and released for use on the authority of the head of Quality Control.

Starting materials in the storage area should be appropriately labelled. Labels should bear at least the following information :

the designated name of product and the internal code reference where applicable;

a batch/control number given at receipt;

where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);

where appropriate, an expiry date or a date beyond which retesting is necessary;

when fully validated computerized storage systems are used, all the above information should not necessarily be

in a legible form on the label.

Labels indicating status should only be attached to starting materials by persons appointed by the person responsible for quality control. Such labels should be of a nature or form which prevents confusion with any similar labels previously used by the material supplier (e.g. they should bear the company name or logo). As the status of the material changes, the status-labels should be changed accordingly.

Stock of starting materials should be inspected at intervals to ensure that the containers are properly closed and labelled, and in good condition. They should be re-sampled and re-tested at intervals given in the starting material specification. Such re-sampling should be initiated by the application of retest labels and/or by similarly effective documentary systems.

Starting materials, particularly those which may deteriorate on exposure to heat, should be stored in strictly air conditioned rooms; materials sensitive to humid and/or light should be stored in appropriately controlled condition.

Starting materials should be issued for use only by an authorized person using an approved procedure. Stock record should be maintained so that stock reconciliations can be made.

Weighing equipment should be verified daily prior to use as accurate and should have capacity, accuracy and precision appropriate to the amount of material to be weighed.

All rejected starting materials should be conspicuously identified, placed separately and should be destroyed or returned to the supplier.

PROCESS VALIDATION

Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded.

When any master processing procedure is adopted, steps should be taken to demonstrate that it is suitable for routine operation and that the defined process, using materials and equipment specified, will consistently yield a product of the required quality.

Significant changes in process, equipment or materials should be accompanied by further validation steps to ensure that the changes continue to yield consistently a product of the required quality.

Processes and procedures should undergo periodic critical revalidation to ensure that they remain capable of achieving the intended results.

PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION

Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapours, sprays or organisms from materials and products in process, from residues on equipment, and from operators' clothing. The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitising materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time.

At every stage of processing, products and materials should be protected from microbial and other contamination.

Cross-contamination should be avoided by appropriate technical or organizational measures , for example:

production in separate building (required for products such as penicillins, sex hormones, certain cytotoxics, live vaccines, live bacterial preparations and some other biologicals as well as blood products);

providing appropriate air-locks and air extraction;

minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;

keeping protective clothing inside areas where products with special risk of cross-contamination are processed;

using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination;

using “self contained system”;

testing for residues and use of cleaning status labels on equipment.

Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.

BATCH AND LOT NUMBERING SYSTEM

There should be a system describing the details of the batch and lot numbering set up with the objective of ensuring that each batch or lot intermediate, bulk or finished product is identified with a specific batch or lot number.

A batch and lot numbering system applied to a processing stage and to the respective packaging stage should be relate to each other.

The batch and lot numbering system should be defined to assure that the same batch or lot number will not be repeatedly used.

Batch or lot numbers allocation should be immediately recorded in a logbook. The record should include date of allocation, product identity and size of batch or lot.

WEIGHING AND DISPENSING

The weighing or counting and dispensing of starting materials, packaging materials, intermediate products and bulk products are considered as part of the production cycle and require complete documentation and reconciliation. The controls governing issuance of these materials for production, from warehouse, dispensing area, or from within the production department, are of critical importance.

The method for handling, weighing, counting and dispensing starting materials, packaging materials, intermediate products, and bulk products should be included in written procedures.

All issuance of starting materials, packaging materials, intermediate products and bulk products including those for additional materials for production orders already dispensed should be properly documented.

Only starting materials, packaging materials, intermediate products and bulk products which have been released by the Quality Control and which are within their shelf-life can be dispensed.

To avoid mix-up, cross-contamination, loss of identity and confusion, only the relevant starting materials, intermediate products and bulk products may be located within the dispensing areas. After weighing, dispensing and labelling, the starting materials, intermediate products and bulk products should be transported and stored in a manner that will preserve its integrity until further processing.

Prior to weighing and dispensing each container of starting materials should be checked for proper labelling, including the approvals label from quality control.

Capacity, accuracy and precision of weighing and measuring equipment used should be appropriate to the amount of materials to be weighed or measured.

For any weighing or measuring operation two persons should independently verify the correctness of the identity and amount of weighed or measured material and the verification recorded.

Weighing and dispensing areas should be maintained in a clean condition. Sterile starting materials to be used for sterile products should be weighed and dispensed in the sterile area (see Glossary: Sterile Room).

Weighing and dispensing operations should be carried out with suitably clean equipment.

Dispensed starting materials, intermediate and bulk products should be rechecked for accuracy and signed by the production supervisor prior to delivery to the production area.

Materials dispensed for each batch should be kept together and conspicuously labelled as such.

RETURNS

All starting materials, packaging materials, intermediate and bulk products returned to storage areas should be properly documented and reconciled.

Starting materials, packaging materials, intermediate and bulk products should not be returned to storage areas unless they meet their defined specification.

PROCESSING

All materials utilized in processing should be checked before use.

Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.

The environment of an area should be monitored and controlled to the degree required for the operation to be performed. Before any processing operation begins steps should be taken to ensure that the work area and equipment are clean and free from any starting material, product, or document not required for the current operation.

All equipment employed in processing should be checked before use. Equipment should be certified in writing as clean before use.

All operations should be performed in accordance with the written procedures. Any deviation should be justified and reported.

Containers and closures used for materials awaiting processing, for intermediate products and for bulk products should be clean and of a nature and type which prevent contamination or deterioration of the product or material.

All containers and equipment holding intermediate products should be properly labelled as to identify the stage of processing. Before applying the labels, all inappropriate labels or marks previously applied should be completely removed.

All intermediate and bulk products should be properly labelled and quarantined until approved and released by quality control.

All required in-process controls should be accurately recorded at the time of performance.

The actual yield of each processing step of a production batch should be recorded and checked against the theoretical yield.

In all stages of processing, particular attention should be paid to the problem of cross-contamination.

Storage time limit and condition of in-process materials should be defined and established.

Critical computer-dependent systems should have alternate systems available in the event of a system failure.

DRY MATERIALS AND PRODUCTS

To overcome problem of dust control and cross-contamination created in handling of dry materials and products special attention is needed in the design, maintenance and use of premises and equipment. Enclosed dust-containing production systems or other suitable methods should be employed if feasible.

Effective air-extraction systems should be installed with discharge points situated to avoid contamination of other products or processes. Effective filtration or other appropriate systems should be installed to retain dust. Tablet and capsule dedusting devices are recommended.

To protect against contamination of the product by fragments of metal or glass special care should be taken. Use of glass equipment is to be avoided. Screens, sieves, punches and dies should be checked for wear or breakage before and after each use.

Care should be taken to guard against tablets or capsules which may lodge and remain undetected in equipment, counters or bulk containers.

Mixing and Granulating

Unless operated as a closed system, mixing, sifting and blending equipment should be fitted with a dust control system.

Critical operating parameters (e.g. time, speed and temperature) for each mixing, blending and drying operation should be laid down in the master production document, monitored during processing and recorded in the batch records.

Filter bags fitted to fluid bed dryers should not be used for different products, without being washed between use. With certain highly potent or sensitizing products, bags specific to one product only should be used. Air entering the drier should be filtered. Steps should be taken to prevent cross-contamination by dust in the air leaving the drier.

Solutions or suspensions should be made and used in a manner which minimizes the risk of contamination or microbial growth.

Compression

Tablet compressing machines should be provided with effective dust control facilities and be situated to avoid product mix-up. Unless the same product is being made on each machine, or unless the compressing machine itself provides its own enclosed air controlled environment, the machines should be situated in separate cubicles.

There should be a suitable physical, procedural and labelling control to prevent mix-up.

Accurate calibrated check weighing equipment should be readily available and used for in-process monitoring of tablets weights.

Tablets removed from a compressing cubicle or station for testing or other purposes should not be returned to the batch.

Rejected or discarded tablets should be placed in containers clearly identifying them as such and the quantity recorded in the batch processing record.

Punches and dies should be examined before each use for wear and compliance with specification. A record of their use should be maintained.

Coating

Air supplied to coating pans for drying purposes should be filtered and of suitable quality.

Coating solutions should be made and used in a manner which will minimize the risk microbial growth. Their preparation and use should be documented.

Hard Capsule Filling

Empty capsule shells should be regarded as starting materials and treated accordingly. They should be stored under conditions which will prevent drying and brittleness or other effects of moisture.

Requirements in Sections 6.82 - 6.87 of Compression also apply to hard capsule filling.

Coated Tablet and Capsule Printing

Special care should be taken to avoid product mix-up during any printing of coated tablets and capsule. Where different products or different batches of the same product are printed at the same time, the operations should be adequately segregated.

The printing ink should be an edible ink.

Care should be taken to avoid mix-up during the inspection, sorting and polishing of capsules and tablets.

LIQUIDS, CREAMS AND OINMENTS (non-sterile)

Liquids, creams and ointments should be produced so as to protect the product from microbial and other contamination. The use of closed systems of production and transfer is strongly recommended. Production areas where the products or open clean containers are exposed should be effectively ventilated with filtered air.

Tanks, containers, pipe-works and pumps should be designed and installed so that they may be readily cleaned and if necessary sanitized. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation.

The use of glass apparatus should be avoided wherever possible. High quality stainless steel is often the material of choice for parts coming into contact with product.

The chemical and microbiological quality of the water used should be specified and monitored. Care should be taken in the maintenance of water system in order to avoid the risk of microbial proliferation. After any chemical sanitization of the water systems, a validated flushing procedure should be followed to ensure that the sanitizing agent has been effectively removed.

Care should be taken when transferring materials through pipelines to ensure that they are delivered to their correct destination.

Where pipelines are used for delivery of ingredients or supply of bulk products, care should be taken to ensure that such systems are easy to clean. Pipe-work should be designed and installed so that it may be readily dismantled and cleaned.

Measuring systems should be verified as accurate. Where dip-sticks are used, they should be used only with the particular vessel for which they have been calibrated. They should be made of suitable non-reactive, non-absorptive material (e.g. not wood).

Care should be taken to maintain the homogenity of mixtures, suspensions, etc. during filling. Mixing and filling processes should be validated. Special care should be taken at the beginning of a filling process, after stoppages and at the end of the process to ensure that homogenity is maintained.

When the bulk product is not immediately packaged, the maximum period of storage and the storage conditions should be specified and adhered to.

PACKAGING MATERIALS

The purchase, handling and control of primary and printed packaging materials as well as other printed materials shall be accorded attention similar to that given to starting materials.

Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorized access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorized personnel following an approved and documented procedure.

Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.

Outdated or obsolete primary packaging material, printed packaging material or other printed material should be destroyed and this disposal recorded.

To avoid mix-up, only one particular printed packaging material or printed material is permitted in a single coding station at a time. Adequate segregation should be maintained between coding stations

PACKAGING OPERATIONS

The function of the packaging operation is to subdivide and package bulk product into finished product. These operations should be performed under strict controls designed to protect the identity, integrity and quality of the final package.

There should be written procedures describing the receipt and identification of bulk and packaging materials, proper controls to assure that the correct bulk, printed and unprinted packaging materials, and other printed materials are used, the required in-process- control the reconciliation of bulk products, printed packaging materials and other printed materials, and final package examination. All packaging operations should proceed in accordance with the instructions given and using the specified materials in the Master Packaging Procedure. Details of the operation should be recorded on the Batch Packaging Record.

Before a packaging operation begins, checks should be carried out to ensure that the work area and equipment are clean and free from any products, product residues or documents not required for the operation.

All deliveries of bulk product, packaging materials and other printed materials should be checked and verified for their correctness against the Master Packaging Procedure or a specific packaging order.

Pre-coding of Components

Labels, cartons, packaging materials and other printed materials that require pre-coding with a batch number or lot number, expiration date, or other information specific to a given packaging order should be strictly controlled at all stages of the process, from the time of delivery from the warehouse until become parts of finished packages or are destroyed.

Packaging materials and other printed materials allocated for pre-coding should be stored in sealed containers within an appropriate area for proper security and segregation.

Pre-coding of packaging materials and other printed materials should take place in an area isolated from other packaging operations.

All pre-coded packaging materials and other printed materials should be checked before transfer to packaging area.

Line Clearance

Immediately prior to the placement of packaging materials and other printed materials on the packaging line, a line clearance check should be made by a designated responsible packaging person in accordance with a written line clearance procedure, approved by the head of Quality Management (Quality Assurance), to:

verify that all materials and packaged products from the previous packaging operation have been removed from the packaging line and line area;

check the line and immediate area for general cleanliness; and

verify that the equipment has been properly cleaned.

Packaging Practices

Risk of packaging errors can be minimized by the following means:

the use of roll-feed labels;

on-line batch coding;

use of electronic code readers and labels counters;

labels and other printed materials designed with distinct marks for different products; and

in addition to visual checks during the packaging run, independent quality control checks during and at the end of the run should be performed.

Products of similar appearance should not be packaged in close proximity unless there is physical segregation.

At each packaging line the name and batch of the product being packaged should be prominently displayed.

Containers in which bulk product, partly packed product, or sub-batch is stored should be labelled or market with an indication of product identity, quantity, batch and status.

Containers to be filled should be supplied to the packaging line or station in a clean condition.

All packaging personnel should be trained to recognize in-process control requirements and report any deviation they may detect while performing their specific responsibilities.

Packaging areas should be cleaned at frequent intervals throughout the work day and at any time a spill of material occurs. Personnel engaged in cleaning should be trained to avoid practices that could cause mix-up or cross-contamination.

Any printed packaging material found in clean-up should be turned over to a supervisor, and be placed in a designated container for reconciliation and destruction at the end packaging run.

Finished or semi-finished packages that are observed off the packaging line should be given to the supervisor and never returned directly of the packaging line. If the package can be identified by the supervisor from its labelling which is of the same lot being packaged and if the package is otherwise in satisfactory condition, it may be returned to the line. Otherwise the material should be scrapped and the amount recorded.

Products filled into their final containers and held awaiting labelling should be segregated and marked so as to avoid mix-up.

Packaging equipment whose parts do not normally come in contact with the bulk product but in which dust, debris, packaging components or product might collect and later fall into the product or otherwise become a contaminant or source of mix-up, should be appropriately cleaned.

Measures should be taken to control the spread of dust during packaging especially of dry products. Segregated packaging areas are necessary for some products e.g. potent low dose or toxic products and sensitizing agents. Compressed air should never be used to clean equipment within an operation packaging area where there is danger of cross-contamination.

Brushes should be restricted in use because of the contamination hazard of hairs or bristles and/or particles held in the brushes.

Personnel should be cautioned not to place packaging components or products in their pockets. Such material should be carried only in their hands or in closed, properly identified containers.

Essential supplies, such as lubricants, adhesive, inks, cleaning fluids, etc. should be kept in containers that look completely different from any container that is used for product packaging and should be prominently and clearly labelled as to their contents.

Completion of the Packaging Operations

On the completion of the packaging operations, the last production package should be carefully checked to confirm that it fully agrees with the Master Packaging Procedure.

Only finished goods from a single packaging operation should be placed on a pallet. Any partial carton and the quantity contained should be indicated on the carton.

The removal of excess packaging components and bulk product, after reconciliation, should be closely supervised to ensure that only the packaging components and bulk product permitted to be returned to the warehouse are saved and that these are properly identified.

The supervisor should oversee the counting and destruction of non-returnable packaging components and bulk product. All unused coded materials should be reconciled and destroyed. Quantities destroyed should be recorded on the batch packaging record.

The supervisor should calculate and record the net used for all packaging components and bulk product.

Any unexplained yield discrepancies or failures to comply with the specifications should be thoroughly investigated, with consideration extended to other batches or other products which might also be affected.

After acceptable reconciliation, the finished product should be delivered to the finished product detention area pending final release by the head of Quality Management (Quality Assurance).

IN-PROCESS CONTROL

To assure batch uniformity and integrity of pharmaceutical products, written procedures describing sample taking, the controls and tests or examinations to be conducted on in-process product of each batch should be performed according to methods approved by the head of Quality Management (Quality Assurance) and the results recorded. Such control is intended to monitor the product yield and validate the performance of the production process that may be responsible for causing variability in the character­istics of in-process products.

Written in-process control procedures should be followed. These procedures should describe the point of sampling, frequency of sampling, number of samples to be taken, specification to be checked, in the limits of acceptability for each specification.

In addition, in-process control should include, but not limited to the following general procedures:

all parameter attributes, product fill or count should be checked at the start of processing or packaging run; and

finished packages should be checked throughout the run at regular intervals to assure that they fully comply with the specifications and that all components are those specified in the Master Packaging Procedure.

During the batch processing and packaging run samples/ packed units should be collected at the beginning, middle and end of operation by appointed persons.

Results of in-process test/inspection should be recorded, and those documents should become a part of the batch record.

In-process specifications should be consistent with the product specifications. They should be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical methods where appropriate.

REJECTED, RECOVERED AND RETURNED MATERIALS

Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by the head of Quality Management (Quality Assurance).

The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record of the reprocessing should be kept.

The recovery of all or part of earlier batches, which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture, should be authorized beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.

The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the head of Quality Management (Quality Assurance).

The recovered batch should not be released until the incorporating batches from which the materials originated have been evaluated and found suitable for use.

Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery with a subsequent batch only after they have been critically assessed by the head of Quality Management (Quality Assurance) in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical re-processing to recover active ingredients may be possible. Any action taken should be appropriately recorded.

FINISHED PRODUCT QUARANTINE AND DELIVERY TO FINISHED STOCK

Finished product quarantine is the last point of control before the product enters the warehouse and becomes available for distribution to the market. Strict controls should be exercised to ensure that the product and its packaging records meet all specified requirements before release to the warehouse.

Written procedures should describe the transfer of finished product into the quarantined area, storage while waiting approval, requirements that should be met for approval, and subsequent transfer to the finished goods warehouse.

Pending release by the Quality Management (Quality Assurance), the entire packaged batch or lot should be detained in the finished goods quarantine.

No product except samples for the quality control unit should be dispensed from any product lot or batch while it is being held in the finished goods quarantine area.

Physical access to the quarantine area should be restricted, and only those persons actually required working in the area or who have been properly authorized to enter the area should be allowed access.

Any finished product that requires special storage conditions should be appropriately labelled to show the required storage conditions, and the material should be stored in quarantine under the specified conditions.

Final release of the product should be preceded by the satisfactory completion of at least the following events:

finished products meet quality control requirements for all processing and packaging specifications;

retention by quality control of sufficient finished market containers as retained samples for future testing;

packaging and labelling meet all requirements as checked by quality control;

the reconciliation of printed packaging components is acceptable; and

marketed packages received in the finished goods quarantine area are reconciled with the amount shown on the transfer documents.

After the Quality Management (Quality Assurance) has approved a batch or a lot, the material should be removed from the finished goods quarantine area to the finished goods storage.

Upon receipt on the finished goods, the warehouse unit should make entry in the corresponding inventory card for the batch received.

CONTROL RECORD FOR SHIPMENT OF PHARMACEUTICAL PRODUCTS

A system designed to control the shipment of pharmaceutical products should assure that the first incoming material is distributed first.

The system should generate records from which the distribution of each batch or lot pharmaceutical product can be readily determined to facilitate investigation or recall if necessary.

Written procedures describing the distribution of pharmaceutical products should be established and followed.

Deviation from first-in first-out concept should be permitted for only short period, and only when authorized by responsible management.

STORAGE OF STARTING MATERIALS, PACKAGING MATERIALS, INTERMEDIATES, BULK PRODUCTS AND FINISHED PRODUCTS

Materials should be stored in an orderly manner to prevent any risk of mix-up or contamination and to facilitate inspection and maintenance.

Materials should be stored off the floor and sufficiently spaced.

The materials should be stored under suitable environmental condition. Any specifically required storage condition should be provided.

Storage conditions for pharmaceutical products and materials should be in compliance with the labelling, which is based on the results of stability testing.

Recorded temperature monitoring data should be available for review. The equipment used for monitoring should be checked at suitable predetermined intervals and the results of such checks should be recorded and retained. All monitoring records should be kept for at least the shelf-life of the stored material or product plus 1 year, or as required by national legislation. Temperature mapping should show uniformity of the temperature across the storage facility. It is recommended that temperature monitors be located in areas that are most likely to show fluctuations.

Outdoor storage is permissible for materials in secured containers (e.g. metal drums) and whose condition will not be adversely affected by exposure to temperature or other conditions.

Storage operations should be adequately segregated from other operations.

All deliveries to storage areas, including returns, should be properly documented.

Each batch of starting materials, packaging materials, intermediates, bulk products and finished products stored in storage areas should have an inventory card. Inventory cards should be periodically reconciled and if there is any discrepancy found it should be recorded and justified when the quantity approved for use is different from the original receipt or delivery. This should be documented with a written explanation.

Storage of Starting Materials and Packaging Materials

Physical or other equivalent validated (e.g. electronic) segregation should be provided for the storage of rejected, expired, recalled or returned materials or products. The materials or products, and areas concerned should be appropriately identified.

All starting materials and packaging materials delivered to storage areas should be checked for proper identity, condition of container and approval of quality control unit.

If the identity or condition of any container of starting materials or packaging materials is suspicious or does not comply with the requirements of identity or condition, that container should be delivered to the quarantine area. The quality control unit shall determine the disposition of the material.

Rejected starting materials and packaging materials should not be stored together with approved materials. They are to be stored in the assigned location for rejects.

Printed materials should be stored in a restrictive storage area and dispensed under strict supervision.

The oldest stock of approved starting materials and packaging materials (FIFO-First In First Out principle) and those nearing expiration date should be used first (FEFO- First Expired First Out principle).

Starting materials and packaging materials should be retested for identity, strength, quality and purity as necessary e.g. after storage periods, or after exposure to air, heat or other condition that may adversely affect their quality.

Storage of Intermediate, Bulk and Finished Products

Intermediates, bulk products and finished products should be quarantined pending quality control testing and disposition.

Each delivery should be checked to verify that the material delivered agrees with the delivery documentation.

Each container of intermediates, bulk products and finished products delivered to the storage area should be checked for proper identification, and condition of containers.

If the identity or condition of any container of intermediates, bulk products and finished products is suspected, or does not comply with the requirements of identity or condition, that container should be retained in the quarantine for quality control inspection and disposition.

DISPATCH AND TRANSPORT

Materials and pharmaceutical products should be transported in such a way that their integrity is not impaired and that storage conditions are maintained.

Special care should be exercised when using dry ice in cold chains. In addition observing to safety precautions, it must be ensured that the materials or product does not come in into contact with dry ice, as this may adversely affect the product quality, e.g. by freezing.

Where appropriate, the use of devices to monitor conditions such as temperature during transportation is recommended. Monitoring records should be available for review.

The dispatch and transport of materials and pharmaceutical products should be carried out only after receipt of a delivery order. The receipt of the delivery order and the dispatch of the goods must be documented.

Dispatch procedures should be established and documented, taking into account the nature of the materials and pharmaceutical products concerned and any special precautions that might be required.

The outside container should offer adequate protection from all external influences and should be indelibly and clearly labelled.

Records for dispatch should be retained, stating at least:

the date of dispatch;

the customer’s name and address;

the product description, e.g. name, dosage form and strength (if appropriate), batch number and quantify; and

the transport and storage conditions.

All records should be readily accessible and available on request.