GOOD MANUFACTURING PRACTICE

GOOD MANUFACTURING PRACTICE

INTRODUCTION:

It is define as “the part of quality assurance which is aimed to ensure that the products are consistently manufactured to the quality appropriate to their intended use “making sure (this is assuring) that medicine is that of right quality. It is the part (and a very big part) that concern all who work in pharmaceutical industry on the manufacture, packing, storage, transportation checking and testing of medicinal product. It is also concern of all those people who assists in the work in for ex: cleaning, maintenance or keeping records. Quite simply it is all about the thing we have to do and the care we have to take to ensure the quality of our products.

REASONS FOR GMP:

We can sum up the reason for GMP in the combination of

§  The poor chance for the patients to detecting any thing wrong.

§  The weakness of product testing because

We can only test the sample

We cannot test for everything

§  The danger to patients of even only a smaller number of defective or wrongly  labeled items in a batch ( it is very difficult to detect a small number of defectives )

That is what GMP is and the reason for it. It is really all about the care and attention necessary to ensure that we get right from the start and “all along the line”.

THE TEN BASIC RULES OF GMP:

1.      Be sure that the written instruction before any job is started.

2.      Always guard against labeling errors.

3.      Always follows those instruction EXACTLY  with no “cutting corners”

4.      Ensure that the correct material being used.

5.      Ensure that the correct equipments is being used, and that is clean.

6.      Prevent contamination and mix up.

7.      Always work accurately and precisely.

8.      Keep the thing (including personnel) clean and tidy.

9.      Always be on the look out for mistakes errors and bad practices and report them immediately (“covering up could cast lives”)

10.  Make clear, accurate records of what has been done and the checks carried out.

GOOD MANUFACTURING PRACTICE – FACTORY PREMISES

SCHEDULE – M rules 71, 74, 76 of D & C Act 1945

1.1 General requirements

a)      Location and surrounding

b)      Building

c)      Water supply

d)     Disposal of waste

1.2 Sterile products

Working space and storage area

1.      Health clothing and sanitation of worker

2.      Medical services

3.      Sanitation in working premises

4.      Equipments

5.      Raw materials

6.      Master formula rerecords

7.      batch manufacturing records

8.      manufacturing operation and records

a.       general control

b.      precaution against contamination and mix up

9.      Reprocessing and recovery

10.  product container and closers

11.  label and printed material

12.  distribution records

13.  record of complaint and adverse reaction

14.  quality control system

General requirements:

Location and surroundings:

Water supply:

The water used in the manufacturing area shall be pure of drinkable quality free pathogenic micro organism.

Disposal of waste: waste water and other residue from the laboratory which might be prejudicial to the worker or to public health shall be disposed of after suitable treatment as per the prevailing requirements of the water pollution control authorities.

Sterile products:

For the manufacture of the sterile products separate enclose area shall be provided with the air lock system for the entry and shall be essentially dust free and ventilated with and air supply for all areas where aseptic manufacturing has to be carried out air supply shall be filter through bacteria proof filter ( HEPA filter) and shall be at pressure higher than in the adjacent area the filter shall be checked for performance an installation and periodically there after, and records there of shall be maintained.

The entire surface in the manufacturing area shall be designed to facilitate cleaning and dis-infections. Routine microbial count to facilitate cleaning and dis-infection. Routine microbial counts of all sterile area shall be carried out during manufacturing operation.

The resultant of each shall be cheeked against established house standard and record maintained. Access to manufacturing area shall be restricted to minimum number of authorized person. Special procedure to be followed for entering and leaving the manufacturing area shall be written down and displayed.

1. Working space and storage area:

The manufacturer shall required adequate working space (manufacturing and quality control) and adequate room for orderly placement of the equipments and materials used in any of the operation for the which it is employed so as to minimize or eliminate any risk of mix up between different drug and materials and to control the possibilities of cross contamination of one drug by another drug that is manufactured, store or handle in the same premises.

There shall be adjusted space in storage area of materials under test, approved and rejected with arrangement and equipment to allow dry, clean and orderly placement of stored material and product where necessary under control temperature and humidity.

2. Healthy clothing and sanitation of workers:

All the person including temporary staff that come in contact with product including raw material under go health check up.

All person shall be free from contagious disease. There clothing shall consist of white or color material made up of cotton or synthetic fabric suitable to the nature of work and climate and shall be clean.

Just before the entry to the manufacturing are there shall be change room (minimum of 8 sq. meter area) separate for each sex with adequate facility for personal cleanliness such as clean towel or hand dryer, soap disinfectant and hand scrubbing brushes so that all personnel change their street cloths and hand wear clean factory cloth. Hand gear and foot wear before entering the manufacturing area and analytical laboratory. The entire worker engaged in filling and sealing of container of sterile preparation wear suitable sterile gowns, hand gear, foot wear and mask of the synthetic fabrics shall be provided to cover the nostrils and mouth during working.

3. Medical services:

the manufacturer also provides:

a)      Adequate facility for first aid

b)      Medical examination of the worker at the time of employment and periodical checkup therefore once in year with particular attention being devoted to freedom from infectious condition. Record there of shall be maintained.

4. Sanitation in the manufacturing premises:

a)      The manufacture area shall not be used for any other purpose.

b)      The manufacturing premises shall be maintained clean and in an orderly manner free from accumulation of dust debris etc.

c)      Eating, chewing, smoking, or any unhygienic practice shall not be permitted in the manufacturing areas.

d)     The manufacturing area shall not be used for general though for personal or for storage of materials expected material being processed.

e)      A routine sanitation program shall be drawn up and observed which be properly recorded and shall indicated

v    Specific area to be cleaned and cleaning intervals

v    Cleaning procedure to be followed including equipment and material to be used for cleaning.

v    Person assigned to and responsible for cleaning operation.

Record compliance in respect of sanitation shall be maintained for inspection.

5. Equipment:

Equipment used for the manufacturing of drugs shall be constructed designed, installed and maintained to

1.      Achieve operational efficiency to attain desire quality.

2.      Prevent physical, chemical and physico-chemical change through surface contact.

3.      Prevent contact of any substance required for operation of the equipment like lubricant etc.

4.      Facilitate through cleaning where ever necessary.

5.      Minimize any contamination of drug and their container during manufacture.

Specific written cleaning instruction for all equipment and utensils should be readily available and the operators are required to be familiar with them.

Manufacturing equipments and utensils shall be thoroughly cleaned and if necessary sterilized in accordance with written and specific instruction, when indicated all equipment should be dismantled and thoroughly clean to provide the carry over residues from previous operation and batches.

The accuracy of the instrument used for specific filling shall be device capable of recording the parameter or with drawn systems to indicate malfunction. These devices shall be calibrated and tested and recorded there of shall be maintained.

6. Raw materials:

The licensee shall keep on inventory of all raw materials to be used at any stage of manufacture of drugs and maintain the record as per schedule U

All such raw material be

a)      Identified and their container examined for damage and assigned control number

b)      Store at optimum temperature and relative humidity

c)      Conspicuously label indicating the number of materials, control numbers, name of manufacture and be labeled under test or approved or rejected

d)     Systematically sampled by quality control person

e)      Test for compliance with required standard of quality

f)       Release form quarantine by quality control personal through written instruction

g)      The stock rotation is so organized that is on the basis of first in first out

h)      The all rejected material are conspicuously identified and are destroyed are returned to the supplier as soon as possible and record maintained there of

7. Master formula records:

The licensee shall maintain MFR relating to all manufacturing procedure for each product which will be prepared and endorsed by the competent technical staff that is head of production and quality control.

The master formula record should have

a)      The patent or proprietary name of the product along with generic name if any strength and the dosage form

b)      A description of identification of the final container packing material label and closer to be used

c)      The identity and quality of the raw material to be used irrespective of whether or not it is appear in the finished product the permissible averages that may be included in   formulation batch should be indicated

d)     Description of the all vessel and equipment and the size used in the progresses

e)      Manufacturing and control instruction along with parameters for critical step such as mixing, drying, blending, sieving, and the sterilizing the product.

f)       The theoretical yield to be expected from the formulation at different stage of manufacture and permissible yield limit.

g)      Detail instruction on precaution to be taken inn manufacturing and storage of drug and semi-finished product.

h)      The requirement of in processes quality control test and analysis to be carried out during each step of manufacture including designation of person or department responsible for execution of such test and analysis.

8. Batch manufacturing records:

The licensee shall maintain BFR as per the schedule U from each batch of drug produced. Manufacturing records are required to provide a complete account of the manufacturing history of each batch of drug showing that it is also been manufactured, tested and analyzed accordance with manufacturing procedure and with written instruction as per the master formula.

9.Manufacturing operation and controls:

General consideration:

      All manufacturing and control shall be carried out under the supervision of competent technical staff approved by licensing authority. Each critical step in formulation like weighing, addition of active should be carried out under in supervision of technical staff.

      Product prepared under aseptic condition is required to be free from pathogen like salmonella, e-coil, pyocyanea etc.

      The content of all the vessels and the container and operating equipment used in manufacturing and storage during various stages should be labeled with a proper batch number, batch size and stage of manufacture. Label shall be attached to the mechanical equipment at the time of operation.

Precaution against contamination and mix up:

The licensee shall prevent cross contamination of drug by appropriate methods:

      Carry out manufacturing operation in separate building or adequate isolating the operating area by total enclosed within building.

      Using appropriate pressure difference in the process area

      Provide suitable exhaust system

d. Designing control as required under master formula including            room temperature. RH, weight variation, dissolution test, mixing time, homogeneity of suspension, volume filled, leakage and clarity shall be checked and recorded.

10. Reprocessing and recovery:

      If product batch has to be reprocessed, reprocessing procedure should be authorized and recorded. An investigation should be carried out in to the cause necessitating, reprocessing and appropriate corrective measure should be taken for the prevention of recurrence.

      Recovery of product residue may be carried out by in sequent batches of the product. If permitted in the master formula.

11. Product container and closer:

      All container and closer shall comply with the pharmacopeias requirement suitable specification, test method, cleaning procedure and sterilization procedure when indicated, shall be used to assure that container, closer and other component part of drugs packages are suitable and they are not  reactive additives, adsorptive or leach to an extent that significantly affect the quality or purity of the drugs.

      When ever bottle being used, the written procedure cleaning should be laid down and followed. Where the bottle is not dried after washing, they should be rinsed with de ionized water or distilled water.

12.  Label and other printed materials:

      Printed and packing material including leaflets should be stored handled and accounted in such a way to ensure that batch packing materials and leaflets relating to different product do not become inter mixed accesses to such material should be restricted to authorized person only.

      Prior to issue, all labels for containers, cartons and boxes and all circular inserts and leaf shall be examined and released as satisfactory for use by the quality control personal.

      To prevent packing and labeling error a known number of labeling and packing unit shall be issued and if required coded such issue shall be made against the written request which indicate the quality and type required.

      Upon the completion of packing and labeling operation, a comparison shall be made between number of packing and labeling unit issued and number of unit label led and packed any significant or unusual dispensing in the number shall be carefully investigated before releasing the final batch.

      Unused, coded and spoiled labels and packing materials shall be destroyed.

      Record shall be maintained for each shipment received of each packing material indicating receipt, examination relating to test and whether accepted or rejected.

13. Distribution records:

Record for distribution of drug shall be maintained for distribution of finished batch of a drug in order to facilitate, promote and recall of the batch if necessary.

14.  Record of complaints and adverse reaction

Record of serious reaction resulting from the use of drug along with comment shall be informed to the concerned licensing authority

15.  The quality control system:

Every manufacturer establish shall have a quality control department supervised by expert staff directly responsible to the management but independent of the other department shall control all raw material, monitor all unprocessed quality check and control the quality and stability of finished product.

The quality control department shall have following duties:

      to prepare detailed instruction in writing for carrying out each test and analysis

      to release or reject each batch of raw material

      to release or reject semi finished product if necessary

      to release or reject packing and labeled material and final container in which drug are packed

      to release or reject each batch of finished product that is ready for distribution

      to evaluate under which raw material, semi and finished product stored

      to evaluate quality and stability of the final product and when necessary of raw material and semi finished product

      to establish self-life and storage requirement on the basis of stability test related to storage condition

      to examine re-tuned product as to whether such product should be released repressed or destroyed

GMP audit

GMP audit is a self inspection programmed in order to detect and to correct any weakness in the quality assurance system of the company. A comprehensive report of all the activities must be reported.

This can be conducted in two ways:

      Conducting survey of manufacturing and operations and their systems to find out the effectiveness of these operations in controlling quality

      Review of some of the products of priority and comparing them with the once originally developed.

The auditing should be done without prejudice and the results should be unbiased. Qualified experienced persons should conduct auditing, operations should be evaluated against approved procedures and standers, the results of the audit are accurate and constructive enough for management to initiate and pursue corrective uelierns. Both positive and negative aspects of the operations must be revealed.

Steps to be followed:

      Imitation, auditor must be familiar with the procedures, functions and mentally prepared about they are going to audit. A questionnaire based on schedule M should be kept for reference.

      The inspection can be made with or without prior notice. But inspection with prior notice is preferred for better chance of success.

      Inspection: Here inspection systems, procedures and records are reviewed. Evaluation is done in a logical manner. After reviewing production, quality control maintenance, materials management should be audited

      Conclusion and reporting: An audit ends up after wrap-up session with the management responsible. The positive and negative aspect should be briefly covered. Reports brief and to the points should be given.

      Follow up: the respective departments must respond to the audit reports and inform the audit team about their actions.

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