cGMP

Eleven Lecture

Intermediate and Bulk Products

1. Intermediate and bulk products should be kept under appropriate conditions 2. Intermediate and bulk products purchased as such should be handled as were starting materials .

Finished Products
1. Finished products should be held in quarantine until their final release . 2. The evaluation of finished products and documentation necessary for release of a product for sale .

Rejected and Recovered Materials

1. Rejected materials and products should be clearly marked as such and stored separately in restricted areas . They should either returned to the suppliers or reprocessed or destroyed . 2. The reprocessing of the rejected products is permitted only if the product quality is not affected i.e. if the product specification is met . Recalled Products Recalled products should be identified and stored separately in a secure area until a decision is taken on their fate .

Documentation
The documents required are : 1. Labels :
Labels applied to containers, equipment or premises should be clear and in companys agreed format . It is helpful in addition to wording on the labels to use colors to indicate status ( quarantined, accepted, rejected, or clean ) . The label for finished product should bearing the following information : a. The name of the drug product b. A list of active ingredients . c. The batch number assigned by the manufacturer . d. The expiry date in an uncooked form . e. Any special storage conditions or handling precautions that necessary f. Directions for use, and warnings and precautions that necessary . g. The name and address of the manufacturer or company .

Specifications and Testing Procedures

1. Testing procedures described in documents should be validated before they are adopted for testing . 2. There should be appropriately authorized and dated specifications including : tests on identity , content uniformity , purity and quality for staring and packaging materials and finished products . Also specification for water , solvent , and reagents used in production . 3. Each specification should be approved and maintained by the quality control unit . 4. Periodic revisions of the specifications may be necessary to comply with new editions of Pharmacopoeia .

Specifications for Starting and Packaging materials

Specifications for starting and primary or printed packaging materials should provide, a description of the materials including : a. The designated name and internal code reference . b. The reference to a pharmacopoeia monograph . c. Qualitative and quantitative requirements with acceptance limits . d. The supplier and the original producer of the materials e. Directions for sampling and testing . f. A specimen of the printed materials . g. Storage conditions and precautions . j. The maximum period of storage before re-examination

Specifications For Finished Products

Specifications for finished products should include : 1. The designated name of the product and the code reference where applicable . 2. The designated name of the active ingredients . 3. The formula or a reference to the formula . 4. A description of the dosage form and package details . 5. Directions of sampling and testing or a reference to procedure . 6. The qualitative and quantitative requirements with acceptance limits . 7. The storage conditions and precautions . 8. The shelf-life .

Master Formulae
A formally authorized master formula should exist for each product and batch size to be manufactured . The master formula should include : 1. The name of the product . 2. A description of the dosage form, strength and batch size 3. A list of all starting materials to be used with the amount of each . 4. A statement of the expected final yield with the acceptable limits . 5. A statement of the processing location and the principle equipment to be used .

Master Formulae ( cont..)

6. The methods or the reference to the methods to be used for preparing the critical equipment e.g. cleaning, assembling, calibrating and sterilization . 7. Detailed stepwise processing instructions . 8. The instructions for any in-process controls with their limits . 9. The requirements for storage of the products, including the container, the labeling etc. . 10. Any special precautions to be observed .

Packaging Instructions
Formally authorized packaging instructions should exist for each product, pack size and type . These should include the following : 1. The name of the product . 2. A description of its pharmaceutical form, its strength and route of administration . 3. The pack size expressed in terms of the number, weight, or volume of the product in the final container . 4. A complete list of all packaging materials required for a standard batch size, including quantities, sizes, and types with the code number relating to the specifications for each packaging materials .

Packaging Instructions ( cont.. )

5. Example of the printed packaging materials indicating where the batch number and expiry date of the product have been marked . 6. Special precautions to be observed including examination of the packaging area and equipment in order to ascertain the line clearance before operations begin . 7. A description of the packaging operation and equipment to be used . 8. Details of in-process controls with instructions for sampling and acceptance limits .

Batch Processing Records

1. A batch processing record should be kept for each batch processed . 2. Before any processing begins a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the process, and the equipment is clean and suitable for use . This check should be recorded . 3. During the processing the following information should be recorded at the time each action is taken : i. The name of the product . Ii. The number of the batch being manufactured . Iii. Dates and times of the beginning of stages and completion of production .

Batch Processing Records ( cont.. )

iv. The name of the person responsible for each stage of production . v. The initials of the operator of different steps of production and of person who checked each of these operations . vi. The batch number / control number and the quantity of each starting material actually weighed . vii. Any relevant processing operation and the major equipment used . viii. The in-process controls performed, and the results obtained . ix. The the yield of the product with explanations for deviations from the expected yield .

Batch Packaging Records

It should be based on the relevant parts of the packaging instructions . It include the following information : 1. Before any packaging operation begins, checks should be made that the equipment and workstation are clear . 2. The name of the product, the batch number, and the quantity of bulk product to be packed, as well as the quantity of the finished product that will be obtained . 3. The date and time of the packaging operations . 4. The name of the responsible person carrying out the packaging operation . 5. The checks made for identity and conformity with the packaging instructions including the in-process controls .

Batch Packaging Records ( cont.. )

6. Details of the packaging operations carried out . 7. Samples of the printed packaging materials used .

8. Notes on any special problems including any deviation from packaging instructions .
9. The quantities of all printed materials and bulk product issued, used, destroyed, or returned to the stock and the quantities of the product obtained to permit an adequate reconciliation .

Standard Operating Procedures ( SOPs)

There should be standard operating procedures and records for the receipt of each delivery of starting material and primary and printed packaging material . The records for the receipts should include :

1. The name of the material on the delivery note and the containers . 2. The in house name / code number of material 3. The date of the receipt 4. The suppliers name and if possible the manufacturers name . 5. The manufacturers batch or reference number 6. The total quantity and the number of containers received . 7. Any relevant comment e.g. state of the containers .

SOP for Sampling

The sampling instructions should include : 1. The method of sampling and the sampling plan . 2. The equipment to be used . 3. Any precautions to be observed to avoid contamination of the material or any deterioration in its quality . 4. The amounts of sample to be taken . 5. Instructions for any required subdivision of the sample 6. The type of sample containers to be used . 7. Any specific precautions to be observed specially in regard to the sampling of sterile material .

Good Practices in Production and Quality Control

1. All handling of materials and products should be done in accordance with written procedures or instructions . 2. Any deviation from instructions should be avoided and if it occur they should be approved in writing by a designated person . 3. Checks on yields and reconciliation of quantities should be carried out to ensure there are no discrepancies outside acceptable limits . 4. Operations on different products should not be carried out simultaneously or consecutively in the same room unless is no risk of mix-up or cross-contamination .

Good Practices in Production and Quality Control ( cont.. )

5. Access to production premises should be restricted to authorized personnel .

6. At all the times during processing all materials, bulk containers, equipment, and rooms used should be labeled that the product or material being processed , its strength, the batch number and the stage of production .
7. In-process controls are performed within the production area .

Prevention of Cross-Contamination and Bacterial Contamination in Production

Cross-contamination can be avoided by technical or organizational measures , for example : 1. Production in segregated areas or by campaign followed by appropriate cleaning . 2. Providing appropriate airlocks, pressure differentials, air extraction . 3. Wearing protective clothing in areas where products with special risk of cross-contamination are processed 4. Using cleaning procedures of known effectiveness . 5. Using closing system of production . 6. Testing for residues . 7. Using cleanliness status labels on equipment .

Good Practices in Quality Control

Quality control is concerned with : Sampling , Specifications , Testing as well as with organization, documentation , and release procedures . Quality control is not confined to laboratory operations, but must be involved in all decisions that may concern the quality of the product . Quality control unit should perform the following : 1. All test procedure for each material or product . 2. Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure .

Good Practices in Quality Control ( cont.. )

3. Sampling should be carried out so as to avoid contamination or other adverse effects on quality . 4. Sampling equipment should be cleaned before and after each use and stored separately from other laboratory equipment . 5. Each sample container should be a label indicating : a. The name of the sample material . b. The batch or lot number . c. The number of container from which the sample has been taken . d. The signature of the person who has taken the sample . e. The date of sampling .

Test Requirements
Before releasing a staring or packaging material for use, the quality control manager should ensure that : 1. The materials have been tested for conformity with specifications for identity , strength , purity and other quality parameters . 2. An identity test should be conducted on a sample from each container of starting materials . 3. Each batch of printed packaging materials must be examined following receipt . 4. A certificate of analysis may be accepted from supplier, certificate must be originals, and the certificate must contain the following information :

Test Requirements ( cont.. )

4. A certificate of analysis may be accepted from supplier, certificate must be originals, and the certificate must contain the following information : 1. Identification of the issuing supplier, signature of the manager or director of QC lab .

2. The name and the batch number of the material tested .

3. A statement of specifications and methods used . 4. A statement of test results obtained and the date of testing .

Stability Studies
1. The QC unit should evaluate the quality and stability of finished products and when necessary of starting materials and intermediate products .
2. The QC unit should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions . 3. A written programmed for ongoing stability determination should be developed and implemented to include :

Stability Studies ( cont.. )

a. A complete description of the drug used in the study . b. A complete testing parameters and methods for potency, and physical characteristics . c. Provision for inclusion of sufficient number of batches d. The testing schedule for each drug . e. Provision for special storage conditions . f. Provision for adequate sample retention . g. A summary of all data generated, including evaluation and the conclusion of the study .