[2.2] PART 2 SECTION 6-8

SECTION 6. PRODUCTION

Production shall follow defined procedures capable to provide assurance of consistently yielding drug products that conform to their specifications.

6.1.1 Equipment shall be technically suitable, well sited (so as not to interfere with other operations), easy to clean and maintain. The design, siting and operation of equipment shall ensure that

no contamination from foreign materials such as rust, lubricants, abraded particles or foreign ingredients should occur.

6.1.2 A high standard of factory sanitation and personal hygiene is necessary to achieve the objectives of protecting each product from contamination by the environment or by the operations and protecting products from cross contamination with other products.

Emphasis in this important areas shall be placed on written programs to ensure that the steps have been logically thought out and validated.

6.1.3 The manufacturer shall clearly define its system of information and control. The documentation system shall:

provide unambiguous sections to be followed, provide confirmation of performance, allow calculation to be checked and to allow the accountability and traceability of operators, materials and batch disposition.

6.1.4 Manufacturing facilities and methods shall be

designed to prevent cross-contamination

6.1.5There shall be sufficient space provided to minimize clutter and untidy work practices to assure orderly material receivals, warehousing and processing activities

. The layout of rooms, corridors and areas, shall provide for logical movement of materials and personnel with minimal traffic and for operations to be carried out in defined areas

6.2 PROCESS VALIDATION

A company should only use validated manufacturing processes. All established processes, materials or products, procedures, activities, systems, equipment or mechanism used in manufacture or control procedures may be validated utilizing a retrospective approach. 

6.2.1 All production procedures shall be properly validated, validation shall be conducted in accordance with previously defined procedures and a record of the results shall be maintained.

The extent and degree of validation depend on the nature and the complexity of the product and process

6.2.2 The validation program and documentation shall provide evidence of the suitability of materials,

the performance and reliability of equipment and systems and the competency of personnel. 

6.2.3 When any master processing procedure is adopted, steps shall 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

6.2.4 Significant changes in process, equipment or materials shall be accompanied by

further validation steps to ensure that the changes continue to yield consistently a product of the required quality.

6.2.5 To ensure that processes and procedures remain capable of achieving the intended results,

These shall routinely undergo critical appraisal

6.3 CONTAMINATION

The presence in a drug product of any contaminant is unacceptable.

The air, water, personnel and all surfaces that come in contact with the product during the manufacturing process are all potential sources of contamination. Regular monitoring of the manufacturing environments shall be instituted to assure that the risk of contamination is detected early and corrective actions are undertaken.  

6.4 BATCH AND LOT NUMBERING SYSTEM

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

6.4.1 A batch and/or lot numbering system applied to a processing state and to the

respective packaging stage shall be related to each other.

6.4.2 The batch and/or lot numbering system shall be defined to assure that the

same batch or lot numbers will not be repeatedly used.

6.4.3 Batch or lot numbers allocation shall be immediately recorded in a logbook or any other means of recording.

The record shall include date of allocation, product identity and size of batch or lot.

6.5 WEIGHING AND DISPENSING

Only approved materials shall be permitted into the dispensary area. The dispensary area is an area that permits a transition from “dirt” bulk storage containers to clean containers for the dispensed materials intended for manufacture. This stage is also the time when pallets constructed of plastic or some other cleanable and impervious materials are used for storage of dispensed materials and transport of bulk dispensed materials throughout the manufacturing areas. The dispensary is an example of a “gray” area that is a transition area from a black area (the warehouse) to a white area (the processing area/s) where the cleanliness level or the reduction of transfer of contaminants is achieved by a simple operation. Another example is operator change and wash procedures. 

6.5.1 The methods for handling, weighing, counting and dispensing raw materials, packaging materials, intermediate products, and bulk products shall be included in

written procedures.

6.5.2 All issuance of raw materials, packaging materials, intermediate products, and bulk products including those for

additional materials for production orders already dispensed shall be properly documented

6.5.3 Only raw materials, packaging materials, intermediate products and bulk products which are approved by

quality control can be dispensed. 

6.5.4 To avoid mix-up, cross-contamination, loss of identity and confusion, only the relevant raw materials, intermediate products and bulk products shall be within the dispensing areas.

After weighing, dispensing and labeling, the raw materials, intermediate products and bulk products shall be transported and stored in a manner that will preserve its integrity until further processing.

6.5.5 Prior to weighing and dispensing, each container of raw materials shall be checked for

proper labeling, including the approval from quality control.

6.5.6 Capacity of weighing and measuring equipment used shall be appropriate to the

amount of materials to be weighed or measured

6.5.7 For any weighing or measuring operation, two persons shall

independently verify the correctness of the identity and amount of weighed or measured materials

6.5.8 Weighing and dispensing areas shall be maintained in a

clean condition

6.5.9 Weighing and dispensing operations shall be carried out with .

clean equipment

6.5.10 Dispensed raw materials, intermediate and bulk products shall be rechecked for identity and accuracy and signed by the

production supervisor or equivalent prior to delivery to the production area

6.5.11 All materials utilized in processing shall be checked for its identity and weight against the batch record before use. The environment of an area shall be

monitored and controlled to the degree required for the operation to be performed. Before any processing operation begin steps shall be taken to ensure that the work area and equipment are free from any material product or document not required for the current operation

6.5.12 All equipment employed in processing shall be checked before use.

Equipment should be certified in writing as clean before use.

6.5.13 All operation shall be performed in accordance with the written procedures.

Any deviation shall be justified and reported

6.5.14 Containers and closures used for materials awaiting processing, for intermediate products and for bulk products shall be clean and of a

nature and type which prevent contamination or deterioration of the product or materials

6.5.15 All containers and equipment holding intermediate products shall be properly labeled as to identify the material and stage of processing.

Before applying the labels, all inappropriate labels or marks previously applied shall be completely removed or crossed out.

6.5.16 All intermediate and bulk products shall be properly labeled and quarantined until

approved and released by quality control

6.5.17 All in-process intermediate and bulk controls shall be accurately recorded at the time of performance.

All step-wise activities in the processing operation indicated in the batch processing record shall be signed and dated at the time of completion of the activity.

6.5.18 The actual yield of each processing step of a production batch shall be

recorded and checked against the theoretical yield

6.5.19In all stages of processing, particular attention shall be given to the

possibility of cross-contamination.

6.6.1 To overcome problems 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 collecting systems or other suitable methods shall be employed.

6.6.2 Effective dust extraction systems shall be installed with discharge points situated to avoid contamination of other products or processes.

Effective filtration or other appropriate systems shall be installed to retain dust.

6.6.3 To protect the product against contamination with fragments of metal, glass or wood, special care shall be taken. .

Use of glass equipment is to be avoided. Screens, punches, sieves and dies shall be checked for wear or breakage before and after each use

6.6.4 Care shall be taken to guard against tablets or capsule that may

lodge and remain undetected in equipment, counters or bulk containers

6.7.1 Mixing, sifting and blending equipment shall be fitted with a

dust control system

6.7.2 Critical operating parameters (e.g. time, speed and temperature) for each mixing, blending and drying operation shall be laid down in the

master production document, monitored during processing and recorded in the batch records

6.7.3 Filter bags fitted to fluid bed dryers shall be specific to

one product use

6.7.4 Solutions or suspensions shall be freshly prepared and

consumed to minimize the risk of contamination or microbial growth

6.8.1Tablet compressing machines shall be provided with

effective dust control facilities.

6.8.2 There shall be a suitable .

physical, procedural and labeling control to prevent mix-up for all in-process tablets

6.8.3 Accurate weighing equipment shall be used for

in-process monitoring of tablet weights.

6.8.4 Tablets removed from a compressing cubicle or station for testing or other purposes

shall not be returned to the batch

6.8.5 Rejected or discarded tablets shall be placed in

containers properly identified and the quantity shall be recorded in the batch processing record

6.8.6 Punches and dies

shall be examined before each use for wear and tear. A record of their use shall be maintained.

6.9.1 Air supplied to coating pans for drying purposes shall be

filtered and of suitable quality.

6.9.2 Coating solutions shall be prepared in a separate cubicle within the coating room and

used immediately to prevent microbial growth. Their preparation and use shall be documented

6.10.1 Empty capsule shells should be regarded as starting materials.

They should be stored under appropriate conditions to prevent drying and brittleness or other effects of moisture.

6.11.1 Liquids, creams and ointments shall use a

closed system of production and transfer to protect the product from contamination

6.11.2 Tanks, containers, pipework and pumps shall be designed and installed so that

they may be readily cleaned and sanitized. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation

6.11.3 High quality stainless steel is the material of choice for

parts coming into contact with product.

6.11.4 The chemical and microbiological quality of the water used shall be

specified, monitored and documented. Water shall be of potable quality and have an acceptable microbial count before usE

6.11.5 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.

Pipework shall be designed and installed so that it may be readily dismantled and cleaned.

6.11.6 Measuring systems shall be verified as accurate. Where dipsticks are used, they shall be used only with the

particular vessel for which they have been calibrated. They shall be made of suitable non-reactive, non-absorptive material (e.g. stainless steel)

6.11.7 Care shall be taken to maintain the homogeneity of mixtures, suspensions, etc. during filling. Mixing and filling processes should be validated.

Special care shall be taken at the beginning of a filling process, after stoppages and at the end of the process to ensure that homogeneity is maintained.

6.11.8 When the finished product is not immediately packaged,

The maximum period of storage and the storage conditions shall be specified and adhered to.

SECTION 7. PACKAGING

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

All packaging operations shall proceed in accordance with a

SOP. Details of the operation shall be recorded on the batch packaging record.

Before a packaging operation begin, checks shall 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.

Finished bulk product and packaging component shall be checked and verified for their

correctness against the master packaging procedure or a specific packaging order.

Labels, cartons and other components that require pre-coding with a batch number or lot number, expiration date, or other information specific to a given packaging order shall be strictly controlled at

all stages of the process, from the time of delivery from the warehouse until they become parts of finished packages

Components for coding shall be stored in

sealed containers within an appropriate area for proper security and segregation.

Coding of components shall take place in

an area isolated from other packaging operations. To avoid mix-up, only one particular printed packaging material is permitted in a single coding station at a time. Adequate segregation shall be maintained between coding stations.

All coded materials shall be checked before

transfer to packaging.

Special emphasis shall be given to the control of pre-printed packaging materials particularly product labels. It is important that there be rigorous control from the draft text through

artwork approval, printing, receipt and quality control, storage, verification, issue, application to the product unit and disposal or return of surplus.

Pre-printed packaging materials shall be identified by a component code number as part of the component printed text. These code numbers shall be

unique to each amendment of text. In addition to the code numbers, there shall be a system of bar codes that is also part of the printed text and is unique for each amendment.

All approved pre-printed packaging materials (including “approved” status labels) shall be stored separately in a

locked area. Access to this area shall be restricted to authorized persons.

Pre-printed materials shall not be

over-printed with a different name, dosage form or strength of the product.

Labels shall be counted on receipt or at the time of issuance or on line. Where batch numbers and expiry date are added to labels off-line, this operation shall be done in a segregated, lockable area which maybe a label store. The coding process shall be

documented and preceded with an area clearance check that follows the standard operating procedure. A known number of each label or pre-printed packaging material shall be issued in sealed containers for each packaging run.

Immediately prior to the placement of materials on the packaging line, a line clearance check shall be made by a designated responsible packaging person in accordance with a written line clearance procedure 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.

The person responsible for the line check shall initial and

date the batch packaging documentation indicating completion of that check

All packaging and labeling materials shall be carefully checked for identity and conformity to the

description in the batch documentation

A check shall be made of the batch number and expiry imprinted on pre-printed packaging materials at start up and regular intervals through the packaging run. The expiry date for a product

should be calculated from the date of the final processing stage of the product before packaging.

Upon completion of the packaging run, unused, un-coded labels and pre-printed packaging materials

shall be counted and held for destruction or be returned to the store. Damaged or defaced pre-printed packaging materials shall be counted or closely estimated.

A reconciliation shall be made between the issued quantities of pre-printed packaging materials and the

respective numbers accounted for on product units, as samples on bulk shipper cartons and also the number destroyed or defaced.

Written in-process control procedures shall be followed. These procedures shall describe the

point of sampling, frequency of sampling, number of samples to be taken, specifications to be checked, and the limits of acceptability for each specification.

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

• the product fill or count shall be checked at the start of a packaging run and

• finished packages shall be checked throughout the run at regular intervals to assure that these fully comply with the specifications and that all components are those specified in the master packaging procedure.

Results of in-process tests/inspection shall be recorded, and these documents shall become a part of the

batch packaging record.

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

shall not be packaged in close proximity, unless there is physical segregation

At each packaging line the _shall be displayed

name and batch of the product being packaged

Containers in which bulk product, partly packed product, or sub-batch is stored shall be

labeled or marked with an indication of product identity, quantity, batch and status.

Containers to be filled shall be supplied to the

packaging line or station in a clean condition.

All packaging personnel shall be trained to recognize

in process control requirements and report any deviation they may detect while performing their specific responsibilities.

Packaging areas shall be cleaned at frequent intervals throughout the workday and at any time a spill of material occurs. Personnel engaged in cleaning shall be

trained to avoid practices that could cause mix-up or cross-contamination.

Any printed packaging material found during clean up operation.

shall be turned over to a supervisor, and be placed in a designated container for reconciliation and destroyed at the end of a packaging run

Products filled into their final containers while waiting for labeling

shall be segregated and marked so as to avoid mix-up. This practice should be avoided and only be instituted in exceptional circumstances.

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, shall be appropriately cleaned.

Measures shall 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

shall never be used to clean equipment within an operation packaging area where there is danger of cross-contamination.

Brushes shall be restricted in use because of the

contamination hazard of hairs or bristles and/or particles held in the brushes.

Personnel shall place packaging components or products in

appropriate properly identified containers.

Essential supplies, such as lubricants, adhesive, inks, cleaning fluids, etc. shall be kept in containers that look

completely different from any container that is used for product packaging and shall be clearly labeled as to their contents.

On the completion of the packaging operation, the last production package shall be

carefully checked to confirm that it fully agrees with the master packaging procedure.

Only finished goods from a single packaging operation shall be placed on a pallet. Any partial carton and the quantity contained shall be indicated on the carton. The removal of excess packaging components and bulk product, after reconciliation, shall 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.