Month: April 2020

Pharmaceutical Plant Complaints and Product Recall as Per GMP

Complaints & Recall

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s, Production, Training, personnel Hygiene, Self-Inspection, quality audits and suppliers’ audit, Personnel and Quality Control. There are various modules of GMP which I will share one after another & today’s module is Complaints & Recall.

Complaints :

What is Product Complaints:   

Any Manufacturing or Packaging related complaints with respect to a Product, including (a) any complaint involving the possible failure of Product to meet any of the specifications or (b) any dissatisfaction or unhappiness with the design, package or labeling of such Product. Complaints comes to the manufacturer after selling of product to the market.

All complaints and other information concerning potentially defective products should be carefully reviewed according to written procedures and the corrective action should be taken.

A person responsible for handling the complaints and deciding the measures to be taken should be allocated, together with sufficient supporting staff to assist him or her.

There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

Special attention should be given to establishing that the product that gave rise to a complaint was defective.

Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for Quality Assurance should normally be involved in the review of such investigations.

If a product defect is discovered or suspected in a batch, consideration should be given to whether other batches should be checked in order to determine whether they are also affected. In particular, other batches that may contain reprocessed product from the defective batch should be investigated.

Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint.

All decisions made and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

Complaints records should be regularly reviewed for any indication of specific or repeating problems that require attention and might justify the recall of marketed products. The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, a suspect product or any other serious quality problems with a product.

Product Recalls :

What is Product Recall :

A product recall is a request from a manufacturer or company to return or removal of a marketed product after the discovery of safety issues or product defects that might threaten the consumer or put the company/seller/ manufacturer at risk of legal action.

There should be a system to recall the products from the market, promptly and effectively, products known or suspected to be defective.

The authorized person should be responsible for the execution and coordination of recalls. He or she should have sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency.

 There should be established written procedures, which are regularly reviewed and updated, for the organization of any recall activity. Recall operations should be capable of being initiated promptly down to the required level in the distribution chain.

An instruction should be included in the written procedures to store recalled products in a secure segregated area while their fate is decided.

All competent authorities of all countries to which a given product has been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective.

The distribution records should be readily available to the authorized person, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall.

The progress of the recall process should be monitored and recorded.

Records should include the disposition of the product and final report should be issued, including a reconciliation between the delivered and recovered quantities of the products.

The effectiveness of the arrangements for recalls should be tested and evaluated from time to time.

Mock recall to be performed at a regular interval to check the effectiveness of the recall.

To know the difference between recall vs Mock recall pl Refer : https://pharmaceuticalupdates.com/2019/01/09/what-is-the-difference-between-recall-mock-recall/

Mock means Make a Duplicate or exact copy of something.

Pharmaceutical Plant Quality Control Requirements as Per GMP

Quality Control

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s, Production, Training, personnel Hygiene, Self-Inspection, quality audits and suppliers’ audit and Personnel. There are various modules of GMP which I will share one after another & today’s module is Quality Control.

General :

QC is the part of GMP concerned with sampling and testing of products and no materials should be used without testing or released. QC is not confined to laboratory operations, but may be involved in many decisions concerning the quality of the product.

Each manufacturer should have a QC function. The QC function should be independent of other departments and under the authority of a person with appropriate qualifications and experience. The basic requirements for QC are as follows: (a) adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (b) To perform qualification and validation; (c) records must be made (manually and/or by recording instruments) demonstrating that all the required sampling, inspecting and testing procedures have actually been carried out and any deviations observed to be recorded and investigated; (d) records must be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications (e) sufficient samples of starting materials and products must be collected to permit future examination of the product if necessary.

Other Responsibilities of Quality Control :

Other QC responsibilities include: (a) establishing, validating and implementing all QC procedures; (b) evaluating, maintaining and storing reference standards for substances; (c) ensuring the correct labelling of containers of materials and products (d) ensuring that the stability of the active pharmaceutical ingredients and products is monitored; (e) participating in the investigation of complaints related to the quality of the product; (f) participating in environmental monitoring;

QC personnel must have access to production areas for sampling and investigation as or whwn ever required.

All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected.

Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling.

Care should be taken during sampling to guard against contamination or mix up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean.

Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment.

Each sample container should bear a label indicating: (a) the name of the sampled material; (b) the batch or lot number; (c) the number of the container from which the sample has been taken; (d) the number of the sample; (e) the signature of the person who has taken the sample; (f) the date of sampling.

Out-of-specification results obtained during testing of materials or products should be investigated in accordance with an approved procedure. Records should be maintained.

Before releasing a starting or packaging material for use, the QC manager should ensure that the materials have been tested for conformity with specifications.

Each batch (lot) of printed packaging materials must be examined following receipt.

Finished products :

For each batch of medicines, there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to release. Products failing to meet the established specifications or any other relevant quality criteria should be rejected.

Quality Control  Record Review :

QC records should be reviewed which is a part of the approval process of batch release before transfer to the authorized person. Any deviation or failure of a batch to meet its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action. Retention samples or Control Samples from each batch of finished product should be kept for at least one year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. Samples of active starting materials should be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases and water) should be retained for a minimum of two years if their stability allows. Retention samples of materials and products should be collected in duplicate of double to perform reanalysis if required.

Stability studies :

QC should evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products.

A written programme for ongoing stability determination should be developed and implemented to include elements such as: (a) a complete description of the medicine involved in the study; (b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability; (c) provision for the inclusion of a sufficient number of batches; (d) the testing schedule for each medicine; (e) provision for special storage conditions; (f) provision for adequate sample retention; (g) a summary of all the data generated, including the evaluation and the conclusions of the study. Stability should be determined prior to marketing and following any significant changes, for example, in processes, equipment or packaging materials.

Pharmaceutical Plant Personnel Requirements as Per GMP

Personnel as per GMP

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s, Production, Training, personnel Hygiene and Self-Inspection, quality audits and suppliers’ audit. There are various modules of GMP which I will share one after another & today’s module is Personnel.

General :

For maintaining a satisfactory Quality system and control of pharmaceutical products depends upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly defined and understood by the persons concerned and shall be recorded.

The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience.

Responsible personnel duties should be assigned based up on Experience and qualifications. The manufacturer or the company should have an organization chart.

All personnel should be aware of the principles of GMP and during joining they have to take the GMP training, personnel hygiene instruction, Good Documentation practice and Data Integrity etc. All personnel should be motivated to support the establishment and maintenance of high quality standards.

Steps should be taken to prevent unauthorized people from entering production, storage and QC areas. Personnel who do not work in these areas should not use them as a passageway.

Key Personnel :

Key personnel include the heads of production, the head(s) of quality unit(s) and the authorized person. The quality unit(s) typically comprises the quality assurance and quality control functions. In some cases, these could be combined in one department. The authorized person may also be responsible for one or more of these quality unit(s). Normally, key posts should be occupied by full-time personnel. The heads of production and quality unit(s) should be independent of each other. Key personnel responsible for supervising the production and quality unit(s) for pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. Their education should include the study of an appropriate combination of: (a) chemistry (analytical or organic) or biochemistry; (b) chemical engineering; (c) microbiology; (d) pharmaceutical sciences and technology; (e) pharmacology and toxicology; (f) physiology; (g) other related sciences. They should also have adequate practical experience in the manufacture and QA of pharmaceutical products.

The heads of the production and the quality unit(s) generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, depending on national regulations: (a) Authorization of written procedures and other documents (b) Monitoring and control of the manufacturing environment (c) Plant hygiene (d) Process validation and calibration of analytical apparatus (e) Training, including the application and principles of QA; (f) Designation and monitoring of storage conditions for materials and products; (g) Performance and evaluation of in-process controls; (h) Retention of records; (i) Monitoring of compliance with GMP requirements; (j) Inspection, investigation and taking of samples in order to monitor factors that may affect product quality.

Responsibilities of Head Production:

The head of production generally has the following responsibilities: (a) to ensure that products are produced and stored in accordance with the appropriate documentation in order to obtain the required quality; (b) to approve the instructions relating to production operations, including the in-process controls, and to ensure their strict implementation; (c) to ensure that the production records are evaluated and signed by a designated person; (d) to check the maintenance of the department, premises and equipment; (e) to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available; (f) to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need.

Responsibilities of Head Quality:

The head(s) of the quality unit(s) generally have the following responsibilities: (a) to approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation to their specifications; (b) to evaluate batch records; (c) to ensure that all necessary testing is carried out; (d) to approve sampling instructions, specifications, test methods and other QC procedures; (e) to approve and monitor analyses carried out under contract; (f) to check the maintenance of the department, premises and equipment; (g) to ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are carried out; (h) to ensure that the required initial and continuing training of quality unit personnel is carried out and adapted according to need; (i) establishment, implementation and maintenance of the quality system; (j) supervision of the regular internal audits or self-inspections; (k) participation in external audit (vendor audit); (l) participation in validation programmes.

The authorized person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval of the release of the finished product for sale or supply.

Assessment of finished products should accept all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack.

No batch of product is to be released for sale or supply prior to certification by the authorized person(s). In certain countries, by law, the batch release is a task of the authorized person from production together with the authorized person from QC.

The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by QA by means of batch review.

Pharmaceutical Plant Self-Inspection, Quality audits and Suppliers’ Audit Requirements as Per GMP

Self-Inspection and Quality audits

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s, Production, Training and personnel Hygiene. There are various modules of GMP which I will share one after another & today’s module is Self-Inspection, quality audits and suppliers’ audit.

What is Self Inspection :

Self Inspection or Internal Audit is a Quality System to check whether activities followed by all departments are according to the written approved procedures and complying with the cGMP and Regulatory Requirements.

For Self Inspection pl Refer : https://pharmaceuticalupdates.com/2019/01/29/self-inspection-or-internal-audit-and-its-requirement-in-pharmaceuticals/

The purpose of self-inspection is to evaluate the manufacturer’s or the plants compliance with GMP in all aspects of production, Quality assurance and Quality Control. The self  inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely and may be in addition, performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP . 

All recommendations for corrective action should be implemented.

The procedure for self-inspection should be documented, and there should be an effective follow-up programme.

Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP requirements covering at least the following items:

(a) Personnel;

(b) Premises including personnel facilities;

(c) Maintenance of buildings and equipment;

(d) Storage of starting materials and finished products;

(e) Equipment and instruments

(f) Production and in-process controls;

(g) Quality control

(h) Documentation;

(i) Sanitation and hygiene;

(j) Validation and revalidation programmes;

(k) Calibration of instruments or measurement systems;

(l) Recall procedures;

(m) complaints management;

(n) Results of previous self-inspections and any corrective steps taken.

Self-inspection Team :

Management should appoint a self-inspection team consisting of experts in their respective fields who are familiar with GMP. The members of the team may be appointed from inside or outside the company.

Frequency of self-inspection :

The frequency with which self-inspections are conducted may depend on company requirements but should preferably be at least once a year. The frequency should be stated in the procedure.

Self-inspection Reports :

A report should be made at the completion of a self-inspection. The report should include:

(a) self-inspection results;

(b) Evaluation and conclusions;

(c) Recommended corrective actions.

There should be an effective follow-up programme. The company management should evaluate both the self-inspection report and the corrective actions as necessary.

Quality Audits :

It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors.

The contract giver shall performed audit at contract acceptors site periodically or before giving contract for manufacturing of products.

Suppliers’ audits and Approval :

The person responsible for QA or CQA should have responsibility, together with other relevant departments, for approving suppliers who can reliably supply Raw and packaging materials that meet established specifications.

Before suppliers are approved and included in the approved suppliers’ list or specifications, they should be evaluated. The evaluation should take into account a supplier’s history and the nature of the materials to be supplied.

If an audit is required, it should determine the supplier’s ability to conform with GMP standards.

Pharmaceutical Plant Training and Personnel Hygiene Requirements as Per GMP

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises, Equipment’s and Production. There are various modules of GMP which I will share one after another & today’s module is Training and personnel Hygiene.

Training:

Training is the main aspects of Good Manufacturing practices and whenever a person joins in an organization he/she required to take the training which includes GMP, Good Documentation practices and job related training etc.

For GDP pl Refer : https://pharmaceuticalupdates.com/2019/01/06/scope-instruction-to-be-followed-for-good-documentation-practices-gdp-in-pharmaceuticals/

The Organization should provide training with a written programme for all personnel those who are going to work in Production, Quality Assurance, Quality control, Engineering and warehouse departments (including the technical, maintenance and cleaning personnel).

Different types of the training are there which includes Induction Training, on job Training, Self Reading Training, External training and Refresher Training etc.

Training shall be conducted as per training Standard Operating Procedure of the respective organization.

For SOP Please Refer : https://pharmaceuticalupdates.com/2019/02/02/standard-operating-procedure-sop-of-standard-operating-procedure-sop/

Besides basic training on the theory and practice of GMP, newly recruited personnel should taken training accordingly to their job responsibilities assigned to them. Training should also be given at a regular interval and as per scheduled and its practical effectiveness to be assessed periodically.

After completion of required training evaluation shall be done and based on evaluation the person can be eligible to perform his/her job responsibility and training record required to be maintained. Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, Hormones, infectious or sensitizing materials are handled, should be given specific training i.e. Entry and Exit to production area, Uses of Personnel protective Equipments and personnel hygiene etc.

Visitors or untrained personnel should preferably not be taken into the production and QC areas. If this is unavoidable, they should be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. They should be closely supervised by the plant personnel.

Consultant and contract staff or casuals should be qualified or trained for the services they provide. Evidence of this should be included in the training records.

Personal Hygiene:

All personnel should undergo health examinations prior to and during employment.

Personnel conducting visual inspections should also undergo periodic eye examinations.

All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing and packing processes. Personnel should be instructed to wash their hands before entering production areas.

Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or medicines until the condition is no longer judged to be a risk.

All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products.

Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials and intermediate or bulk product.

To ensure protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and if necessary, disinfected or sterilized.

Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines should not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality. Personal hygiene procedures, including the wearing of protective clothing, should apply to all persons entering production areas, whether they are temporary or full-time employees or non-employees, e.g. contractors’ employees, visitors, senior managers and inspectors.

Pharmaceutical Plant Production Requirement as Per GMP

Production system as per GMP

Earlier I have shared you the GMP Requirement for Pharmaceutical plant premises & Equipment’s. There are various modules of GMP which I will share one after another & today’s module is Production.

General Requirements :

The handling of materials and products, such as receipt, quarantine, sampling, storage, labeling, dispensing, processing, packaging and cleaning should be done in accordance with written procedures or instructions (Standard Operating Procedure) and, where necessary, recorded.

Deviation from instructions or procedures should be avoided as far as possible and If deviations occur, they should be in accordance with an approved procedure. The deviation shall be raised and approved and the required Corrective and Preventive action shall be taken.

For Deviation Refer : https://pharmaceuticalupdates.com/2019/02/22/procedure-for-handling-of-deviations-in-pharmaceuticals/

Yields and reconciliation of quantities should be carried out at different stages of Manufacturing and packing to ensure that there are no discrepancies outside acceptable limits.

Operations on different products should not be carried out simultaneously in the same room or area as there are the chances of mix up or cross-contamination.

During manufacturing and packing the major items of equipments, the rooms, packaging lines being used should be labelled or otherwise identified with an indication of the product or material being processed. The labelled should contain Material name or product name, Batch number, Stage of manufacturing, done by, checked by and date etc to avoid mix-up.

Access to production premises should be restricted to authorized personnel.

In-process controls are usually performed within the production area.

Prevention of cross-contamination and bacterial contamination during production :

When dry materials and products are used in production, special precautions should be taken to prevent the generation and spreading of dust. Provision should be made for proper air control (e.g. supply and extraction of air and dust extraction system).

Contamination of a starting material or of a product by another material or product must be avoided.

Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example: (a) carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations and certain other biologicals); (b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure; (c) providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems; (d) minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air; (e) wearing protective clothing where products or materials are handled; (f) using cleaning and decontamination procedures of known effectiveness; (g) using a “closed system” in production; (h) testing for residues; (i) using cleanliness status labels on equipment.

Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOPs. Production areas where products are processed should undergo periodic environmental monitoring (e.g. for microbiological and particulate matter, where appropriate).

Processing or Manufacturing operations :

Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels and documents which are not required for the current operation.

Line clearance should be taken before starting of any activity for the respective areas and equipments where batch processing shall be carried out.  

For Line clearance Refer : https://pharmaceuticalupdates.com/2019/02/06/line-clearance-procedure-in-pharmaceuticals/

Any necessary in-process checks and environmental controls should be carried out and recorded during activity and at regular intervals.

Defective equipment should be withdrawn from use until the defect has been rectified. After use, production equipment should be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination.

Production equipment should be thoroughly cleaned according to a fixed schedule or after product to product change over or batch to batch change over or based upon validity of Cleaned equipment or Dirty equipment’s.

Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated according to a fixed schedule i.e. Calibration and daily Verification of weighing balances, Calibration of In process checks instruments like Disintegration tester, Friability, LOD apparatus, Vernier  caliper, Hardness and Thickness Tester, leak test apparatus .

The cleaning, usage and preventive maintenance details shall be mentioned in the respective equipment logbooks separately which shall content Date, Product name, Batch number, cleaning or usage activity start time, End time, activity done by, checked by and type of cleaning or preventive maintenance etc. Any significant deviation from the expected yield should be recorded and investigated.

Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

Water sampling should be done at a regular interval or as per scheduled in production area

Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at prespecified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated on a label attached to the instrument.

Repair and maintenance operations should not present any hazard to the quality of the products.

Packaging operations :

When the packaging is going to start  particular attention should be given to minimizing the risk of cross-contamination and mix ups. Different products should not be packaged in  close proximity unless there is physical segregation or an alternative system that will provide equal assurance.

Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents used previously and which are not required for the current operation. The line clearance should be performed according to an appropriate procedure and checklist, and recorded.

The name and batch number of the product being handled should be displayed at each packaging station or line.

Normally, filling and sealing should be followed as quickly as possible by labelling. If labelling is delayed, appropriate procedures should be applied to ensure that no mix ups or mislabelling can occur.

The correct performance of any printing (e.g. of code numbers or expiry dates) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular intervals.

Before start of packing activity the Specimen proof like Foil carton, leaflet, label etc should be checked by both production and Quality assurance and same shall be preserved along with batch record Regular online control of the product during packaging should include at a minimum checks on: (a) the general appearance of the packages; (b) whether the packages are complete; (c) whether the correct products and packaging materials are used; (d) whether any overprinting is correct; (e) the correct functioning of line monitors. Samples taken away from the packaging line should not be returned.

Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and recorded before batch release to market.

Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded.

The excess printed packing materials like Aluminum foil, PVC/PVDC can be returned to warehouse with material return note.  

Production records should be reviewed as part of the approval process of batch release and  any deviation or failure of a batch to meet production specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy.

Pharmaceutical Plant Equipment’s Requirement as Per GMP

GMP

Below given details are the Good Manufacturing Practices requirements for the Pharmaceutical Plant Equipment’s

Equipment’s must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and any adverse effect on the quality of products.

Equipment should be installed in such a way as to minimize any risk of error or of contamination.

Equipment should be Qualified before use i.e. Design, Installation, operational and Performance Qualification of the equipment’s shall be completed before use.

Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow i.e. purified water, Potable water and Compressed Air etc.

All service pipework and devices should be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids.

Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated according to a fixed schedule i.e. Calibration and daily Verification of weighing balances, Calibration of In process checks instruments like Disintegration tester, Friability, LOD apparatus, Vernier  caliper, Hardness and Thickness Tester, leak test apparatus .

Production equipment should be thoroughly cleaned according to a fixed schedule or after product to product change over or batch to batch change over or based upon validity of Cleaned equipment or Dirty equipment’s.

The cleaning, usage and preventive maintenance details shall be mentioned in the respective equipment logbooks separately which shall content Date, Product name, Batch number, cleaning or usage activity start time, End time, activity done by, checked by and type of cleaning or preventive maintenance etc.

Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to an extent that would affect the quality of the product.

Material of construction of the equipment’s contact part should be Stainless Steel 302, 304, 304L, 316, 316L and Teflon etc.

Defective equipment should be removed from production and QC areas. If this is not possible, it should be clearly labelled as defective to prevent use.

A periodic preventive maintenance schedule shall be prepared for each equipment’s and after each  preventive maintenance equipment’s shall be cleaned.

Closed equipment should be used whenever appropriate. Where open equipment is used or equipment is opened, precautions should be taken to minimize contamination.

Non-dedicated equipment should be cleaned according to validated cleaning procedures between being used for production of different pharmaceutical products to prevent cross-contamination.

Current drawings of critical equipment and support systems should be maintained.

Reference WHO Technical Report Series : TRS986annex2

https://pharmaceuticalupdates.com/2020/04/03/good-manufacturing-practices-for-pharmaceutical-products-plant-premises-requirements/

Pharmaceutical Plant Premises Requirement as Per GMP

GMP

Below given details are the GMP requirements for the Pharmaceutical Plant premises or campus and Premises or campus must be located, designed, constructed, adapted and maintained to afford the Operations to be carried out.

General Requirements :

The layout and design of premises must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross contamination, build-up of dust or dirt, and in general, any adverse effect on the quality of products.

Where dust is generated (e.g. during sifting, weighing, mixing and processing operations, or packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning.

Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation.

Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products.

Premises should be cleaned and, where applicable, disinfected according to detailed written procedures and records should be maintained.

Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.

Premises should be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There should be a procedure for rodent and pest control. Premises should be designed to ensure the logical flow of materials and personnel movement.

Additional Areas :

Rest and refreshment rooms should be separate from manufacturing and control areas.

Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users and Toilets should not communicate directly with production or storage areas.

Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.

Storage Areas :

Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation which includes starting and packaging materials, intermediates, bulk and finished products, products in quarantine, and released, rejected, returned or recalled products.

Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, sufficiently lit and maintained within acceptable temperature & Relative humidity limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, controlled, monitored and recorded where appropriate.

Receiving and dispatch bays should be separated and should protect materials and products from the weather. Receiving areas should be designed and equipped to allow containers of incoming materials to be cleaned, if necessary, before storage.

Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel.

Segregation should be provided for the storage of rejected, recalled, or returned materials or products.

Highly active and radioactive materials, narcotics, other dangerous medicines, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas.

Printed packaging materials and similar looking packing materials are considered critical to the pharmaceutical product hence its labelling and special attention should be taken to safe and secure storage of these materials.

There should normally be a separate sampling area for starting materials. (If sampling is performed in the storage area, it should be conducted insuch a way as to prevent contamination or cross-contamination.)

Weighing Areas :

The weighing of raw material, intermediate, or a drug substance should be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas.

Production Areas :

In order to minimize the risk of a serious medical hazard due to cross contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g. penicillins) or biological preparations  (e.g. live microorganisms). The production of certain other highly active products, such as some antibiotics, hormones, cytotoxic substances and certain non-pharmaceutical products, should not be conducted in the same facilities. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products.

Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.

Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and disinfection.

Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

Drains should be of adequate size and designed and equipped to prevent back-flow. Open channels should be avoided where possible, but if they are necessary they should be shallow to facilitate cleaning and disinfection.

Production areas should be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and humidity where necessary) appropriate to the products handled. These areas should be regularly monitored during both production and non-production periods to ensure compliance with their design specifications.

Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix ups, contamination or cross-contamination.

Production areas should be well lit, particularly where visual online controls are carried out.

Quality control Areas :

QC laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other.

QC laboratories should be designed to suit the operations to be carried out and sufficient space should be given to avoid mix ups and cross contamination.

There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records.

The design of the laboratories should take into account the suitability of construction materials, prevention of fumes, and ventilation. There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological and radioisotope laboratories.

A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors, or where it is necessary to isolate the instruments.

Reference WHO Technical Report Series : TRS986annex2

Importance of Preventive Maintenance in Pharmaceuticals

Preventive Maintenance

What is Preventive Maintenance:

Preventive maintenance is the maintenance that is regularly performed on a piece of equipment or Instruments to reduce the possibility of its failure or breakdown during running. It is performed while the equipment is still working so that it does not break down unexpectedly.

Procedure for Performing preventive maintenance :

List out all equipments and prepare the preventive maintenance schedule in daily, weekly, monthly, quarterly, half-yearly and yearly, wherever applicable.

The checks to be performed during preventive maintenance and their frequencies shall be as per the equipment/vendors recommendation and based on the experience of engineering team.

The preventive maintenance schedule will be carried out with in ± two days for weekly preventive maintenance and with in ± seven days for Monthly, Quarterly, ± thirty days Half-yearly and Yearly preventive maintenance if any production emergency activities are planned.

The Daily, Weekly, Monthly, Quarterly, Half-yearly and Yearly preventive maintenance of all Process equipments and Utility equipments is the responsibility of the technical assistants or machine operators and verification of the same is the responsibility of respective department incharge.

The maintenance personal after carrying out the preventive maintenance shall record the details in equipment usage log book of the respective equipment’s or instruments. The same shall be checked by concerned production in charge.

After preventive maintenance the respective area and equipment’s shall be cleaned in case of Manufacturing area equipments parts as it is coming in product contact.

Ensure the availability of equipment’s for preventive maintenance as per the schedule and Plan advance planning is required for any external support to carry out the preventive maintenance.

Check the availability of spares or consumables, which are planning to change during the preventive maintenance of any machinery.

The person who carries the preventive maintenance shall fill the preventive maintenance checklist of particular equipment and shall update the activity executed date in planner also.

Different formats required to be filled for different equipment’s or instruments or utilities and required formats shall be issued from Quality assurance as per requirements.

After completion of preventive maintenance status label of the equipment’s or instruments or utilities hall be updated accordingly.

For those equipments which are not in use for more than three months, the preventive maintenance shall not be done and further scheduled preventive maintenance shall be discontinued.

Concerned department personnel shall raise the work request memo for carrying out the preventive maintenance of those “Not in use’ equipment before taking into production. Further preventive maintenance schedules shall be maintained from that instance.

A separate preventive maintenance schedule shall be prepared for the newly installed equipment from the date of respective preventive maintenance SOP implementation or after performance qualification of the equipment’s.

For obsolete equipment’s the preventive maintenance shall be discontinued from the date of obsolete and the schedule for particular equipment shall be appended with a comment “obsolete” and duly signed by concerned maintenance executive.

preventive maintenance planner shall be updated annually & same scheduled shall be followed for the same year & when ever any new equipment is qualified the preventive maintenance shall be updated through add on and checklist shall be prepared.

Importance of preventive maintenance and Conclusion :

preventive maintenance is required as per regulatory and Good Manufacturing practice requirement (GMP).

It will save cost of organization or decreased the downtime i.e An unexpected failure in equipment can ideal the equipment, ideal of employee, can stop or delay production etc. so a periodic preventive maintenance plan can save a company or organization money .

Improved Safety measures i.e Preventive maintenance improves the safety of equipment’s and therefore the safety of company workers resulting in fewer on the job injuries and accidents.

Improved Reliability i.e Customers can count on a company to deliver products, materials, or service on time, without unnecessary delays.

Conservation of Assets i.e Most equipment’s are not cheap now a days, so a company should cares for its equipment, the longer it will last. Preventive maintenance will increase the life of equipment resulting in reduced costs and increased profit.

But in most of the company or organization preventive maintenance are not performed as per scheduled and preventive maintenance checklist are being filled and dates are being changed in the equipment’s.

All the checkpoints mentioned in the preventive maintenance checklist are not followed which can lead to the breakdown of the equipment during running.

In most cases as per my experience i have observed that equipment’s are being used for 24 hours or 365 days and the user departments are not handed over the equipment to engineering department for planned preventive maintenance.

Management of the company or organization should take it seriously and should run the machine by considering preventive maintenance schedule.