GMP Requirements: Good Manufacturing Practices (GMP) comes in Schedule M in Drugs and Cosmetics Act 1940 and Rules 1945. GMPs are the requirements that the drug and methods/control/facilities used in their manufacturing, processing, and packaging conform to practice that will assure the safety and efficacy of the product. GMPs include a set of practices that ensure quality at every level of operation in the industry. It takes into consideration the following aspects:
Different parts of GMP are:
1. General provisions:
The regulation in this part contains the minimum cGMP for the preparation of drug products for administration to human beings or animals.
2. Organization and personnel:
The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of quality products rely upon people. For this reason, there must be sufficient qualified personnel with the necessary qualifications and practical experience to carry out all the tasks which are the responsibility of the manufacturer.
- Important personnel includes; the head of Production, the Head of Quality Control, and the head of Engineering.
- The manufacturer should provide training for all the personnel.
- Personnel working in areas where, contamination is a hazard, e.g. clean areas or areas where, highly active, toxic, infectious, or sensitizing materials are handled should be given specific training.
- Detailed hygiene programs should be established and adapted to the different needs within the industry. It should include; procedures relating to the health, hygiene practices, and clothing of personnel.
- All personnel should receive medical examinations upon recruitment.
- Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.
- Eating, drinking, chewing, smoking, or storage of food, drink, smoking materials, or personal medication in the production and storage areas should be prohibited.
- Direct contact should be avoided between the operator’s hands and the exposed product.
- Personnel should be instructed to use the handwashing facilities.
3. Building and Facilities:
Table: Building and Facilities Requirement under GMP
|Building Requirements||Facilities Requirement under GMP|
|Premises||Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. The layout and design of the premises must aim to minimize the risk of errors and permit effective cleaning and maintenance to avoid cross-contamination, the buildup of dust or dirt, and in general, any adverse effect on the quality of products.|
|Design and construction features||The building should have adequate space for orderly placement of equipments and materials to prevent mix-up. It should be designed in such a way as to facilitate cleaning, maintenance, and proper operation. Floors, walls, ceiling surfaces should be easily cleanable. Temperature and humidity control should be provided.|
|Lighting||Adequate lighting should be provided in all the areas.|
|Ventilation, Air filtration||An Air ventilation system should be provided. Equipment for control over pressure, microorganism, dust, humidity, and temperature should be provided.|
|Plumbing||Potable water should be supplied. Drains should be of adequate size and preventive measures should be taken to prevent back-siphonage.|
|Sewage and refuse||Sewage waste and other refused material from building and intermediate premises should be disposed of in a safe and sanitary manner.|
|Washing and toilet facilities||Suitable washing facilities should be provided including; hot and cold water, soap or detergent, air drier, towel, and clean toilet facilities easily accessible to the working area.|
|Sanitation||Any building used in manufacturing, processing, packing, or holding of a drug product should be maintained in a clean and sanitary condition. Such buildings should be free of infestation by rodents, birds, insects, and other vermin.|
|Maintenance||1. The building should be maintained in a good state. |
2. Premises should be carefully maintained, ensuring that repair and maintenance operations do not cause any hazard to the quality of products.
3. Lighting, temperature, humidity, and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage or the accurate functioning of equipment.
4. Premises should be designed and equipped to afford maximum protection against the entry of insects or other animals.
5. Steps should be taken to prevent the entry of unauthorized people.
6. Interior surfaces (walls, floors, and ceilings) should be smooth, free from cracks and open joints and should not shed particulate matter, and should permit easy and effective cleaning and if necessary, should be disinfected.
7. Pipework, light fittings, ventilation points, and other services should be designed and sited to avoid the creation of recesses that are difficult to clean.
8. The weighing of starting materials should be carried out in a separate weighing room designed for that use.
9. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk, and finished products, products in quarantine, released, rejected, and returned.
10. Segregated areas should be provided for the storage of rejected. recalled or returned materials or products.
11. Highly active (controlled) materials or products should be stored in safe and secure areas.
12. Quality control laboratories should be separated from production areas.
13. Rest and refreshment rooms should be separate from other areas.
14. Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users.
15. Animal houses should be well isolated from other areas, with separate entrances (animal access) and air handling facilities.
Equipments must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance to avoid cross-contamination, the buildup of dust or dirt.
Design, size, and location: Equipment used in manufacturing, processing, packaging, or holding of a drug product should be of appropriate design, adequate size, and easy to clean.
Construction: Equipment should be constructed so that surface that, contacts materials should not be reactive.
Cleaning and maintenance: Equipments and utensils should be cleaned, maintained, and sanitized at intervals to prevent contamination that may alter the safety, identity. strength and quality of drug product.
Automatic, mechanical, and electronic equipment: Computers or related systems may be used in manufacturing and other processes. It should be routinely calibrated, inspected, or checked to assure proper performance.
5. Control of components, drug product containers, and closures:
- There should be written procedures describing in detail receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures.
- It should not be reactive, additive, or absorptive strength, quality, or purity of the herbal drug.
- It should protect against environmental hazards.
- It should be clean and sterilized.
6. Production and process control:
- There should be a written procedure for production and process control designed to assure that the drug products have the identity, strength, quality, and purity that they are represented to possess.
- To assure the batch uniformity and integrity of drug products, written procedures have to be established to monitor the output and to validate the performance of the manufacturing process responsible for causing variability.
7. Packaging and labeling control:
- Labeling and packaging materials should be examined or tested upon receipt and before use in the packaging or labeling of drug products.
- Records should be maintained for each shipment.
- Packaged and labeled products have to be examined after finishing the operations to assure that containers and packages in the lot have the correct label.
- The label should bear an expiry date determined by the appropriate stability testing method.
8. Holding and Distribution:
- Warehouse procedure includes: Storage of drug products under appropriate conditions of temperature, humidity, and light so that, the identity, purity of drug products are not affected.
- The distribution procedure includes: Oldest approved stock of drug products is distributed first. The distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.
9. Laboratory Control:
- Laboratory control should include; appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials conform to appropriate standards of identity, strength, quality, and purity.
- There should be a written testing program designed to assess the stability characteristics of drug products.
- Animals used in the testing should be maintained and controlled in a manner that assures their suitability for their intended use.
10. Records and Reports:
- Production, quality control, and distribution records are required to be maintained and should be retained for at least 1 year after the expiration of the batch. (For OTC drugs: 3 years).
- All maintained records should be available for authorized inspection.
- A written record of major equipment cleaning, maintenance should be included in 1 individual equipment log, that shows the date, time, product, and lot number of each batch processed.
- The identity and quantity of each shipment of each lot of components, with receiving code and date of receipt should be maintained.
- To assure uniformity from batch to batch, master production and control records for each drug product including; each batch size, should be prepared, dated and signed by one person and checked by a second person, which includes:
- Name and strength of the product, description of the dosage form.
- Name and weight of active ingredient per dosage unit.
- Complete a list of components designated by names or codes.
- A statement of the theoretical yield.
- A description of drug products, containers, closures, and packaging materials.
- Complete manufacturing, control instructions, sampling and testing procedure, specifications, and precautions to be followed.
11. Returned and Salvaged drug product:
- Returned drug products should be identified as such and held. Returned product should be destroyed unless examination, testing, or other investigations prove that the drug product meets appropriate standards of safety, identity, strength, quality, or purity.
- A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristics.
- Records of returned products should be maintained and should include; the name, potency, lot number, reason for return, quantity returned, date of disposition, and ultimate disposition of drug product.
- Drug Product Salvaging: Drug products that have been subjected to improper storage conditions including: extreme temperature, humidity, smoke, fumes, pressure, age, due to natural disasters, fire, accidents, and other hazards should not be salvaged and returned to the market place.
- When a product has been subjected to such conditions, salvaging operation may be conducted only if there is: Evidence from laboratory tests and assays that the product meet all applicable standards of identity, strength, quality, and purity.
Quality Assurance (QA):
Quality Assurance (QA) testing is an activity to ensure that an organization is providing the best possible product to customers. QA focuses on improving the processes to deliver quality products to the customer. An organization has to ensure, that processes are efficient and effective as per the quality standards defined for products.
Quality assurance has a defined cycle called PDCA (Plan-Do-Check-Act) cycle or Deming cycle. The phases of this cycle are:
- Plan: Organization should plan and establish the process-related objectives and determine the processes that are required to deliver a high-quality end product.
- Do: Development and testing of processes and also “do” changes in the processes.
- Check: Monitoring of processes, modify the processes and check whether it meets the predetermined objectives.
- Act: Implement actions that are necessary to achieve improvements in the processes.
The system of quality assurance suitable to the manufacture of the pharmaceutical product should ensure that:
- Pharmaceutical products are designed and developed in compliance with the requirements of GMP including: GLP and GCP.
- Production and quality control operations are properly documented.
- Managerial responsibilities are specified in job descriptions.
- Arrangements are made for the manufacturing, supply, and use of correct starting and packaging material.
- There should be proper quality control on raw materials, intermediate products, bulk products, and packaging material.
- Calibration and validation are carried out.
- Finished products are correctly processed and checked.
- Test every production batch.
- There should be satisfactory facilities to ensure the safety, quality, and efficacy of products.
- There must be a procedure for self-inspection.
- Deviations are reported, investigated, and documented.
- There is a system for approving changes that may have an impact on product quality.
Quality Assurance in production consists of the following steps:
- General requirements: Handling of materials and products such as; receipt, sampling, storage should be done by a written procedure.
- Prevention of cross-contamination and bacterial contamination in production: Protective clothes should be worn, provided with appropriate airlock and pressure differentials.
- Processing operations: Intermediate and bulk products: In-process control and environmental control.
- Packaging operation: Filling, Sealing, printing, embossing should be distinct and resistant to fading or erasing.
Quality audit is the process of regular examination of a quality system carried out by an internal or external quality auditor or an audit team. This helps to determine if the pharmaceutical industry complies with the defined quality system processes and can involve procedural or results-based assessment criteria.
A quality audit consists of:
- Preparing a list of items (procedures, equipment set-ups, quality records, measurements, etc.)
- Checking and going to the areas responsible for these items for an actual check or audit of these items.
Types of Quality Audit:
Objectives of Auditing:
- To determine the conformity or non-conformity of the quality system.
- To determine the effectiveness of the implemented quality system.
- To provide the audit team with an opportunity to improve the quality system.
- To meet the regulatory requirements.
- To permit the listing of audited organizations in a register.
Steps to perform a Quality Audit:
- To plan and prepare for the audit.
- To arrange and announce the audit.
- To arrive at the site of the audit, meet people and explain the purpose.
- To perform a quality audit.
- Informal oral report finding.
- A formal report with recommendations.
- Finally to follow up on the deficiencies.
Standard Operating Procedure (SOP) for Auditing:
Every pharmaceutical company prepares a Standard Operating Procedure (SOP) for auditing which includes:
- Information regarding the company policy about auditing.
- Composition of auditing team.
- Scope of audit.
- Selected area subjected to auditing.
- Frequency of auditing.
- Written reports on audits including their distribution.
- Corrective actions of deficiencies.
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