Pharma Pathfinder by Chandrasekhar Panda

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1.4. Good Manufacturing Practices applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, until the product discontinuation.

The product quality system can extend to the pharmaceutical development life-cycle stages and shall facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. All parts of the product quality system shall be adequately resourced and maintained, including being provided with sufficient competent personnel, suitable premises, equipment and facilities.

The product quality system appropriate to the manufacture of pharmaceutical products shall ensure that—
Product realization is achieved by designing, qualifying, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes;
Product and process knowledge is managed throughout all lifecycle stages;
Pharmaceutical products are designed and developed in a way that takes into account, the requirements of GMP and other GXPs such as those of Good Laboratory Practices (GLP) and Good Clinical Practices (GCP);

(d) Production and quality control operations shall be clearly specified in a written form and GMP Requirements are adopted;

(e) Managerial responsibilities are clearly specified in the job descriptions;

(f) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is the correct material from the approved supply chain;

(g) All necessary controls on starting materials, intermediate products, and bulk products and other in process controls, calibrations and validations are carried out;

(h) The finished product is correctly processed and checked, according to the defined procedures;

(i) Pharmaceutical products are not sold or supplied before the authorised persons have certified that each production batch has been produced and controlled in accordance with the requirements of the licence and other applicable regulations relevant to the production, control and release of pharmaceutical products;

(j) Processes are in place to ensure the management of outsourced activities;

(k) Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf-life;

(l) There is a procedure for self-inspection or quality audit that regularly appraises the effectiveness and applicability of the product quality system;

(m) Product and processes are monitored and the results taken into account in batch release, in the investigation of deviations and, with a view to taking preventive action to avoid potential deviations occurring in the future;

(n) Arrangements are in place for the prospective evaluation and approval of planned changes and their approval prior to their implementation, taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality;

(o) Regular reviews of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and identifying where there is a need for improvement;

(p) A state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality;

(q) Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge;

(r) There is a system for QRM; and

(s) Deviations, suspected product defects and other problems are reported, investigated and recorded. An appropriate level of root cause analysis is applied during such investigations. The most likely root causes shall be identified and appropriate corrective and preventive actions shall be identified and taken. The effectiveness of corrective and preventive actions shall be monitored.

1.6. There shall be periodic management reviews, with the involvement of senior management, of the operation of the product quality system to identify opportunities for continual improvement of products, processes and the system itself. Unless otherwise justified, such reviews shall be conducted at least annually.

1.7. The product quality system shall be defined and documented. A quality manual or an equivalent documentation shall be established and shall contain a description of the quality management system including management responsibilities.

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2. Quality Risk Management (QRM):

2.1. Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.

2.2. Quality Risk Management shall ensure that the-

(a) Evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient;

(b) Level of effort, formality and documentation of the QRM process is commensurate with the level of risk.

2.3. Product quality review-

2.3.1. Regular, periodic or rolling quality reviews of all pharmaceutical products, including products for export only, shall be conducted with the objective of verifying the consistency of the existing process and the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements.

2.3.2. Such reviews shall normally be conducted and documented annually, taking into account previous reviews, and shall include at least,-

(a) Review of starting materials and packaging materials used for the product, especially those from new sources and in particular the review of supply chain traceability of active substances;

(b) A review of critical in-process controls, and finished product results;

(d) A review of all significant deviations or non-conformity, the related investigations and the Effectiveness of resultant corrective and preventive actions taken;

(e) A review of all changes made to the processes or analytical methods;

(f) A review of dossier variations submitted, granted or refused;

(g) A review of the results of the stability monitoring programme and any adverse trends;

(h) A review of all quality related returns, complaints and recalls and the investigations performed at the time;

(i) A review of adequacy of any other previous corrective actions on product processes or Equipment;

(j) Post marketing commitments for new dossiers and variations to the dossiers;

(k) The qualification status of relevant equipment and utilities, e.g., heating, ventilation and air

conditioning, water or compressed gases and a review of the results of monitoring the output of such equipment and utilities; and

(l) A review of technical agreements to ensure that they are up to date.

2.3.3. The manufacturer shall evaluate the results of the review and an assessment shall be made as to whether corrective and preventive actions or any revalidation shall be undertaken, under the product quality system. Corrective and preventive actions shall be completed in a timely and

Effective manner, according to documented procedures. There shall be procedures for the on-going management and review of these actions, and the effectiveness of these procedures shall be verified during self-inspection.

Quality reviews may be grouped by product type e.g., solid dosage forms, liquid dosage forms, or sterile products, where scientifically justified. There shall be a technical agreement in place between the various parties that defines their respective

Responsibilities in producing the quality review. The authorised person responsible for final batch

Certification shall ensure that the quality review is performed in a timely manner and is accurate.

3. Good manufacturing practices for pharmaceutical products:

3.1. Good manufacturing practices is that part of quality management which ensures that products are consistently produced and controlled according to the quality standards appropriate to their intended use as required by the conditions of licence, clinical trial permission or product specifications. Good manufacturing practices are concerned with both production and quality control. Good manufacturing practices are aimed primarily at managing and minimizing the risks inherent in pharmaceutical manufacture to ensure the quality, safety and efficacy of products. Under Good manufacturing practices—

(1) all manufacturing processes are clearly defined, systematically reviewed for associated risks in the light of scientific knowledge and experience and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

(2) Qualification and validation are performed;

(3) All necessary resources are provided, including the following, namely-

(a) Sufficient and appropriately qualified and trained personnel;

(b) Adequate premises and space;

(d) Appropriate materials, containers and labels;

(e) approved procedures and instructions;

(f) Suitable storage and transport;

(g) Adequate personnel, laboratories and equipment are in process controls; and

(h) Books necessary for ensuring compliance with the requirements relating to product development, manufacturing and quality control testing such as the Drugs and Cosmetics Act, 1940, the Drugs Rules, 1945, the Indian Pharmacopoeia (Current Edition) and other relevant books and guidance documents officially issued by the Ministry of Health and Family Welfare, Government of India;

(4) Instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

(5) Procedures are carried out correctly and personnel are trained to do so;

(6) Records are made (manually or by recording instruments or by both) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected. Any significant deviations are fully recorded and investigated with the objective of determining the root cause and appropriate corrective and preventive action is implemented;

(7) Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

(8) The proper storage and distribution of the products which minimises any risk to their quality;

(9) All system is available to recall any batch of product from sale or supply; and

(10) Complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures are taken in respect of the defective products to prevent recurrence.

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4. Sanitation and hygiene:

A high level of sanitation and hygiene shall be practiced in every aspect of the manufacture of drugs. The scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection and anything that could become a source of contamination to the product. Potential sources of contamination shall be eliminated through an integrated comprehensive programme of sanitation and hygiene.

5. Qualification and validation:

5.1. In accordance with GMP, each pharmaceutical company shall identify what qualification and validation work is required to prove that the critical aspects of their particular operation is controlled.

5.2. The key elements of a qualification and validation programme of a company shall be clearly defined and documented in a validation master plan.

5.3. Qualification and validation shall establish and provide documentary evidence that—

(a) The premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for good manufacturing practices [design qualification (DQ)];

(b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications [installation qualification (IQ)];

(c) The premises, supporting utilities and equipment operate in accordance with their design Specifications [operational qualification (OQ)];

(d) A specific process shall consistently produce a product meeting its predetermined specifications and quality attributes [process validation (PV), also called performance qualification (PQ)].

5.4. Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, may affect the quality of the product, directly or indirectly, shall be qualified and validated.

5.5. Qualification and validation shall not be considered as one-off exercises. An on-going programme shall follow their first implementation and shall be based on a periodic review.

5.6. The commitment to maintain continued validation status shall be stated in the relevant company documentation, such as the quality manual or validation master plan.

5.7. The responsibility for performing validation shall be clearly defined.

5.8. Validation studies are an essential part of good manufacturing practices and shall be conducted in accordance with predefined and approved protocols.

5.9. A written report summarizing the results recorded and the conclusions reached shall be prepared and stored.

5.10. Processes and procedures shall be established on the basis of the results of the validation performed.

5.11. Particular attention shall be paid to the validation of analytical test methods, automated systems and cleaning procedures.

5.12. The premises, equipment or process system, facility qualification and validation shall be carried out.

6. Complaints and adverse reaction:

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

6.2. A person responsible for handling the complaints and deciding the measures to be taken shall be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorised person, the latter shall be made aware of any complaint, investigation or recall.

6.3. There shall 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.

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

6.5. Any complaint concerning a product defect shall be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control (QC) shall normally be involved in the review of such investigations.

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

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

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

6.9. Complaint records shall be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products.

6.10. The licensing authorities shall be informed if a manufacturer is considering action following the faulty manufacture, product deterioration, a suspect product or any other serious quality problems with a product.

6.11. The licensee shall have a pharmacovigilance system in place for collecting, processing and forwarding the reports to the licensing authorities for information on the adverse drug reactions emerging from the use of drugs manufactured or marketed by the licensee.

7. Product recalls:

7.1. There shall be a system to recall from the market, products known or suspected to be defective.

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

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

7.4. An instruction shall be included in the written procedures to store recalled products in a secure segregated area.

7.5. The licensing authorities shall be informed of any intention to recall the product because it is, or is suspected of being, defective.

7.6. The distribution records shall be readily available to the authorized person, and they shall contain sufficient information on wholesalers and directly supplied customers to permit an effective recall.

7.7. The progress of the recall process shall be monitored and recorded. Records shall include the disposition of the product. A final report shall be issued, including reconciliation between the delivered and recovered quantities of the products.

7.8. The effectiveness of the arrangements for recall shall be tested and evaluated from time to time.

7.9. A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, up to the retail level within the shortest period. The licensee may make use of both print and electronic media in this regard.

7.10. There shall be an established written procedure in the form of Standard Operating Procedure for effective recall of products distributed by the licensee. Recall operations shall be capable of being initiated, so as to effectively reach at the level of each distribution channel.

7.11. The distribution records shall be readily made available to the persons designated for recall.

7.12. The designated person shall record a final report issued, including reconciliation between the delivered and the recovered quantities of the products.

7.13. The effectiveness of the arrangements for recall shall be evaluated from time to time.

7.14. The recalled products shall be stored separately in a secured segregated area pending final decision on them.

8. Change control:

8.1. A formal change control system shall be established to evaluate all changes that may affect the production and control of the product.

8.2. Written procedures shall cover the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials and computer software.

8.3. Any proposals for relevant changes to GMP shall be drafted, reviewed and approved by the appropriate organisational units and reviewed and approved by the quality units.

8.4. The potential impact of the proposed change on the quality of the intermediate or Active Pharmaceutical Ingredient (API) or finished product shall be evaluated. A classification procedure may help in determining the level of testing, validation and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on their nature and extent and the effect of these changes may have on the process. Scientific judgement shall be used to determine what additional testing and validation studies are appropriate to justify a change in a validated process.

8.5. When implementing the approved changes, measures shall be taken to ensure that all the documents are affected by the changes as revised.

8.6. After the change has been implemented there shall be an evaluation of the first batch produced or tested under the change.

8.7. The potential for critical changes to affect established retest or expiry dates shall be evaluated. If necessary, samples of the intermediate or API or finished product produced by the modified process can be placed on an accelerated stability programme or can be added to the stability monitoring programme or both.

9. Production under loan licence or contract and contract analysis and other activities:

9.1. Principle- Production under loan licence or contract and contract analysis and any other activity covered by good manufacturing practices must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product, or work or analysis, of unsatisfactory quality.

9.2. General-

9.2.1. All arrangements for production under loan licence or contract and analysis, including technology transfer and any proposed changes in technical or other arrangements, shall be in accordance with the licence for the product concerned.

9.2.2. The contract shall permit the loan licensee or contract giver to audit the facilities and activities of the manufacturing facility provider or contract acceptor or mutually agreed sub-contractors.

9.2.3. In the case of contract analysis, the final approval for release must be given by the authorized person in accordance with good manufacturing practices and the licence as specified in the contract.

9.3. Loan licensee or contract giver-

9.3.1. The product quality system of the loan licensee or contract giver shall include the control and review of any outsourced activities. The contract giver is responsible for assessing the legality, suitability and competence of the manufacturing facility provider or contract acceptor to successfully carry out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of good manufacturing practices incorporating quality risk management principles are followed.

9.3.2. The loan licensee or contract giver shall provide the manufacturing facility provider or contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the licence and any other legal requirements. The loan licensee or contract giver shall ensure that the manufacturing facility provider or contract acceptor is fully aware of any hazards associated with the product, work or tests that might pose a risk to premises, equipment, personnel, other materials or other products.

9.3.3. The loan licensee or contract giver shall review and assess the records and results related to the outsourced activities. The contract giver shall ensure that all the products and materials delivered by the manufacturing facility provider or contract acceptor have been processed in accordance with good manufacturing practices and the licence; comply with their specifications and that the product has been released by the authorised person in accordance with good manufacturing practices and the licence.

9.3.4. The loan licensee or contract giver shall monitor and review the performance of the manufacturing facility provider or contract acceptor including the implementation of any needed improvements and their effectiveness.

9.3.5. The loan licensee or contract giver is responsible for ensuring that the manufacturing facility provider or contract acceptor understands that his or her activities may be subject to inspection by the competent authorities.

9.4. Manufacturing facility provider or contract acceptor-

9.4.1. The manufacturing facility provider or contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the loan licensee or contract giver. Contract manufacture shall be undertaken only by a manufacturer who holds a valid manufacturing licence.

9.4.2. The manufacturing facility provider or contract acceptor shall not pass to a third party any of the work entrusted to him or her under the contract without the loan licensee or contract giver’s prior evaluation and approval of the arrangements. Arrangements made between the manufacturing facility provider or contract acceptor and any third party shall ensure that information and knowledge, including that from assessments of the suitability of the third party, are made available in the same way as between the original loan licensee or contract giver and contract acceptor.

9.4.3. The manufacturing facility provider or contract acceptor shall refrain from any activity (including unauthorized changes outside the terms of the contract) that may adversely affect the quality of the product manufactured or analyzed or both for the loan licensee or contract giver.

9.5. Contract-

9.5.1. There must be a written contract between the loan licensee or contract giver and the manufacturing facility provider or contract acceptor which clearly establishes the responsibilities of each party, covering the outsourced activities, the products or operations to which they are related, communication processes relating to the outsourced activities and any technical arrangements made in connection with it.

9.5.2. The contract must clearly state the way in which the authorised person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the licence.

9.5.3. Technical aspects of the contract shall be drawn up by competent persons with suitable knowledge of pharmaceutical technology, analysis and good manufacturing practices.

9.5.4. All arrangements for production and analysis must be in accordance with the licence and agreed by both parties.

9.5.5. The contract shall clearly describe who is responsible for contracted activities e.g., knowledge management, technology transfer, supply chain, sub-contracting, testing and releasing materials and undertaking production and quality control, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract shall state whether or not the manufacturing facility provider or contract acceptor shall take samples at the premises of the manufacturer.

9.5.6. Manufacturing, analytical and distribution records, and reference samples, shall be kept by, or be available to, the loan licensee or contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect, or to investigating a suspected product or laboratory fraud, must be accessible and specified in the procedures of the loan licensee or contract giver.

9.5.7. The contract shall describe the handling of starting materials, intermediate, bulk and finished products, if they are rejected. It shall also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected.

10. Self-inspection, quality audits and suppliers’ audits and approval:

10.1. The purpose of self-inspection is to evaluate the manufacturer’s compliance with good manufacturing practices in all aspects of production and QC. The self-inspection programme shall be designed to detect any shortcomings in the implementation of good manufacturing practices and to recommend the necessary corrective actions. Self-inspections shall be performed routinely, and may be, in addition, performed on special occasions e.g., in the case of product recall or repeated rejections, or when an inspection by the regulatory authorities is announced. The team responsible for self-inspection shall consist of personnel who can evaluate the implementation of good manufacturing practices objectively.

All recommendations for corrective action shall be implemented. The procedure for self-inspection shall be documented and there shall be an effective follow-up programme.

10.2. Items for self-inspection-Written instructions for self-inspection shall be established to provide a minimum and uniform standard of requirements. These may include questionnaires on good manufacturing practices requirements covering at least the following items, namely:-

(a) Personnel;

(b) Premises including personnel facilities;

(d) Storage of starting materials and finished products;

(e) Equipment;

(f) Production and in-process controls;

(g) Quality control (QC);

(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) Labels control; and

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

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10.3. Self-inspection team- Management shall 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.

10.4. Frequency of self-inspection- The frequency with which self-inspections are conducted may depend on company requirements but shall be at least once in a year. The frequency shall be stated in the procedure.

10.5. Self-inspection report- A report shall be made at the completion of a self-inspection. The report shall include the following, namely:-

(a) Self-inspection results;

(b) Evaluation and conclusions; and

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

10.7. Quality audit- 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.

10.8. Suppliers’ audits and approval–

10.8.1. The person responsible for quality control shall have responsibility, together with other relevant departments, for approving suppliers who can reliably supply starting and packaging Materials that meet established specifications.

10.8.2. Before suppliers are approved and included in the approved suppliers’ list or specifications, they shall be evaluated. The evaluation shall take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it shall determine the supplier’s ability to conform with good manufacturing practices standards.

11. Personnel:

11.1. Principle-The establishment and maintenance of a satisfactory system of Quality Assurance (QA) and the correct manufacture and control of pharmaceutical products and active ingredients rely 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 shall be clearly defined and understood by the persons concerned and recorded as written descriptions.

11.2. General-

11.2.1. The manufacturer shall have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual shall not be so extensive as to present any risk to quality.

11.2.2. Responsible staff shall have its specific duties recorded in written descriptions and adequate authority to carry out its responsibilities. Its duties may be delegated to designated deputies with a satisfactory level of qualifications. There shall be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of good manufacturing practices. The manufacturer shall have an organisation chart.

11.2.3. All personnel shall be aware of the principles of good manufacturing practices that affect them and receive initial and continuing training, including hygiene instruction, relevant to their needs. All personnel shall be motivated to support the establishment and maintenance of high quality standards.

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

11.3. Key personnel-

11.3.1. Key personnel include the heads of production, the heads of quality units and the authorised person. The quality units typically comprise the QA and QC functions. In some cases, these could be combined in one department. The authorised person may also be responsible for one or more of these quality units. Normally, key posts shall be occupied by full-time personnel. The heads of production and quality units shall be independent of each other. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated.

11.3.2. Key personnel responsible for supervising the production and quality units for pharmaceutical products shall possess the qualifications and experience as specified under the rules. Their education shall include the study of an appropriate combination of the following, namely:-

(a) Chemistry (analytical or organic) or biochemistry;

(b) Chemical engineering;

(d) Pharmaceutical sciences and technology;

(e) Pharmacology and toxicology;

(f) Physiology; or

(g) Other related sciences.

They shall also have adequate practical experience in the manufacture and QA of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they shall perform their duties under professional guidance.

The scientific education and practical experience of experts shall be such, so as to enable them to exercise independent professional judgement, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and QC of pharmaceutical products.

11.3.3. The heads of the production and the quality units shall have shared, or jointly exercised, Responsibilities relating to quality. They may include the following, namely:-

(a) Authorization of written procedures and other documents, including amendments;

(b) Monitoring and control of the manufacturing environment;

(d) Process validation and calibration of analytical apparatus;

(e) Training, including the application and principles of QA;

(f) Approval and monitoring of suppliers of materials;

(g) Approval and monitoring of contract manufacturers;

(h) Designation and monitoring of storage conditions for materials and products;

(i) Performance and evaluation of in-process controls;

(j) Retention of records;

(k) Monitoring of compliance with good manufacturing practices requirements; and

(l) Inspection, investigation and taking of samples in order to monitor factors that may affect product quality.

11.3.4. The head of production has the following responsibilities, namely:-

(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;

(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 are made available; and

(f) To ensure that the required initial and continuing training of production personnel is carried Out and adapted according to need.

11.3.5. The heads of the quality units generally have the following responsibilities, namely:-

(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;

(d) To approve sampling instructions, specifications, test methods and other QC procedures;

(e) To approve and monitor analysis 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); and

(l) Participation in validation programmes.

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

11.3.7. Assessment of finished products shall embrace 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.

11.3.8. No batch of product is to be released for sale or supply prior to certification by the authorized persons.

11.3.9. The authorised person responsible for approving a batch for release shall always ensure that the following requirements have been met:-

(a) The licence and the approval requirements for the product have been met for the batch Concerned;

(b) The principles and guidelines of GMP, as laid down in this Part, have been followed;

(d) All the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records;

(e) Any planned changes or deviations in manufacturing or QC have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification and approval by the licensing authority;

(f) Any additional sampling, inspection, tests and checks have been carried out or initiated, as Appropriate, to cover planned changes and deviations;

(g) All necessary production and QC documentation has been completed and endorsed by Supervisors trained in appropriate disciplines;

(h) Appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff;

(i) Approval has been given by the head of quality control; and

(j) All relevant factors have been considered, including the factor associated with the output batch directly under review (e.g., sub-division of output batches from a common input, factors associated with continuous production runs).

11.3.10. 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 quality assurance by means of batch review.

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11.4. Training-

11.4.1. The manufacturer shall provide training in accordance with a written programme for all Personnel whose duties take them into manufacturing areas or into the control laboratories (including the technical, maintenance and cleaning personnel) and for other personnel as required.

11.4.2. Besides basic training on the theory and practice of good manufacturing practices, newly recruited personnel shall receive training appropriate to the duties assigned to them. Continuous training shall also be given, and its practical effectiveness be assessed periodically. Approved training programmes shall be available. Training records shall be kept.

11.4.3. 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, shall be given specific Training.

11.4.4. The concept of quality assurance and all the measures which aid its understanding and Implementation shall be fully discussed during the training sessions.

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

11.4.6. Consultant and contract staff shall be qualified for the services they provide. Evidence of this shall be included in the training records.

11.5. Personal hygiene-

11.5.1. All personnel, prior to and during employment, as appropriate, shall undergo health checkups. Personnel conducting visual inspections shall also undergo periodic eye checkups.

11.5.2. All personnel shall be trained in the practices of personal hygiene. A high level of personal hygiene shall be observed by all those concerned with manufacturing processes. In particular, personnel shall be instructed to wash and sanitise their hands before entering production areas.

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

11.5.4. All employees shall 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.

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

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

11.5.7. Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines shall not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality.

11.5.8. Personal hygiene procedures, including the wearing of protective clothing, shall apply to all persons entering production areas, whether they are temporary or full-time employees or nonemployees, e.g., contractors’ employees, visitors, senior managers and inspectors.

12. Premises:

12.1. Principle- Premises must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. They shall conform to the conditions as laid down in the Factories Act, 1948 (63 of 1948).

12.2. General-

12.2.1. The layout and design of premises must aim to minimise 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.

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

12.2.3. Premises shall be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products.

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

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

12.2.6. Premises shall be cleaned and, where applicable, disinfected according to detailed written Procedures and records shall be maintained.

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

12.2.8. The design, installation, qualification and maintenance of the Heating, Ventilation, Air Conditioning (HVAC) systems of the manufacturing plant shall be carried out.

12.2.9. Premises shall be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There shall be a procedure for rodent and pest control.

12.2.10. Premises shall be designed to ensure the logical flow of materials and personnel.

12.3. Ancillary areas-

12.3.1. Rest and refreshment rooms shall be separate from manufacturing and control areas.

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

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

12.3.4. Animal houses shall be well isolated from other areas, with separate entrance (animal access) and air-handling facilities.

12.4. Storage areas-

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

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

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

12.4.4. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physical quarantine shall give equivalent security.

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

12.4.6. Highly active and radioactive materials, narcotics, other dangerous drugs, and substances Presenting special risks of abuse, fire or explosion shall be stored in safe and secure areas.

12.4.7. Printed packaging materials are considered critical to the conformity of the pharmaceutical Product to its labelling and special attention shall be paid to sampling and the safe and secure storage of these materials.

12.4.8. There shall normally be a separate sampling area for starting materials. If sampling is Performed in the storage area, it shall be conducted in such a way so as to prevent contamination or cross-contamination.

12.5. Weighing areas-The weighing of starting materials and the estimation of yield by weighing shall 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.

12.6. Production areas-

12.6.1. In order to minimise 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 sensitising 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 non-pharmaceutical products, shall 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, shall not be allowed in premises used for the manufacture of pharmaceutical products.

12.6.2. Premises shall preferably be laid out in such a way so 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.

12.6.3. The adequacy of the working and in-process storage space shall 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 minimise the risk of omission or wrong application of any of the manufacturing or control steps.

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

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

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

12.6.7. Production areas shall 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, where necessary, humidity) appropriate to the products handled, to the operations undertaken and to the external environment. These areas shall be regularly monitored during both production and non-production periods so as to ensure compliance with their design specifications.

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

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

12.7. Quality Control (QC) Areas-

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

12.7.2. QC laboratories shall be designed to suit the operations to be carried out in them. Sufficient space shall be given to avoid mix ups and cross-contamination. There shall be adequate Suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records.

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

12.7.4. 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.

13. Equipment:

13.1. Equipment 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 minimise 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.

13.2. Equipment shall be installed in such a way so as to minimise any risk of error or of contamination.

13.3. Fixed pipework shall be clearly labelled to indicate the contents and, where applicable, the direction of flow.

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

13.5. Balances and other measuring equipment of an appropriate range and precision shall be available for production and control operations and shall be calibrated according to a fixed schedule.

13.6. Production equipment shall be thoroughly cleaned according to a fixed schedule.

13.7. Laboratory equipment and instruments shall be suited to the testing procedures undertaken.

13.8. Washing, cleaning and drying equipment shall be chosen and used so as not to be a source of contamination.

13.9. Production equipment shall 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.

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

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

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

13.13. Current drawings of critical equipment and support systems shall be maintained.

14. Materials:

14.1. The main objective of a pharmaceutical plant is to produce finished products for patients’ use from a combination of materials (starting and packaging).

14.2. Materials include starting materials, packaging materials, gases, solvents, process aids, reagents and labelling materials.

14.3. No materials used for operations such as cleaning, lubrication of equipment and pest control shall come into direct contact with the product. Where possible, such materials shall be of a suitable grade (e.g., food grade) to minimise health risks.

14.4. All incoming materials and finished products shall be quarantined immediately after receipt or processing, until they are released for use or distribution.

14.5. All materials and products shall be stored under the appropriate conditions established by the manufacturer, and in an orderly fashion, to permit batch segregation and stock rotation by a first-expire, first-out rule.

14.6. Water used in the manufacture of pharmaceutical products shall be suitable for its intended use. There shall be validated system for treatment of water drawn from own or any other source to render it potable in accordance with the standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce purified water conforming to Pharmacopoeial specification. Purified Water so produced shall only be used for all the operations except washing and cleaning operations where potable water may be used. Water shall be stored in tanks, which do not adversely affect quality of water and ensure freedom from microbiological growth. The tank shall be cleaned periodically and records maintained by the licensee in this behalf. Good manufacturing practices regarding the design, installation and operation of pharmaceutical water systems including guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients and dosage forms, shall be ensured.

14.7. The purchase of starting materials is an important operation that shall involve staff who has a particular and thorough knowledge of the products and suppliers.

14.8. Starting materials shall be purchased only from the approved suppliers and, where possible, directly from the producer. It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is beneficial for all critical aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements as well as complaints and rejection procedures, to be contractually agreed between the manufacturer and the supplier.

14.9. For each consignment, at a minimum, the containers shall be checked at least for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier’s labels.

14.10. All incoming materials shall be checked to ensure that the consignment corresponds to the order. Containers shall be cleaned where necessary and labelled, if required, with the prescribed information. Where additional labels are attached to containers, the original information shall not be lost.

14.11. Damage to containers and any other problem that might adversely affect the quality of a material shall be recorded and reported to the Quality Control Department and investigated.

14.12. If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release.

14.13. Starting materials in the storage area shall be appropriately labelled. Labels shall bear at least the following information, namely:—

(a) The designated name of the product and the internal code reference where applicable;

(b) The batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any, documented so as to ensure traceability;

(d) Where appropriate, an expiry date or a date beyond which retesting is necessary. When fully Validated computerized storage systems are used, not all of the above information need be in a Legible form on the label.

14.14. Only raw materials which have been released by the QC Department and which are within their shelf life shall be used.

14.15. The raw materials other than APIs, if released by QC Department without specific batch testing, for use in manufacturing, it shall be based on vendor approval and statistical data analysis of earlier test results of such material for release.

14.16. There shall be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn shall be identified.

14.17. Only starting materials released by the QC Department and within their shelf-life shall be used.

14.18. Starting materials shall be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.

14.19. Each dispensed material and its weight or volume shall be independently checked and recorded.

14.20. Materials dispensed for each batch of the final product shall be kept together and conspicuously labelled as such.

14.21. The purchase, handling and control of primary and printed packaging materials shall as for starting materials.

14.22. Particular attention shall be paid to printed packaging materials. They shall be stored in secure conditions so as to exclude the possibility of unauthorized access. Roll feed labels shall be used wherever possible. Cut labels and other loose printed materials shall be stored and transported in separate closed containers so as to avoid mix ups. Packaging materials shall be issued for use only by designated personnel following an approved and documented procedure.

14.23. Each delivery or batch of printed or primary packaging material shall be given a specific reference number or identification mark.

14.24. Out-dated or obsolete primary packaging material or printed packaging material shall be destroyed and its disposal shall be recorded.

14.25. All products and packaging materials to be used shall be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions.

14.26. All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.

14.26.1. Whenever bottles are being used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, they shall be rinsed with purified water or water for injection, as the case may be.

14.26.2. The requirements mentioned in this Part do not include requirements of machinery, equipment and premises required for preparation of containers and closures for different dosage forms and categories of drugs. The suitability and adequacy of the machinery, equipment and premises shall be examined taking into consideration the requirements of each licensee in this respect.

14.26.3. Packaging material to be used for pharmaceutical products shall be in accordance with the requirements prescribed in Indian Pharmacopoeia (IP).

14.27. Intermediate and bulk products shall be kept under appropriate conditions.

14.28. Intermediate and bulk products purchased shall be handled on receipt as they were starting materials.

14.29. Finished products shall be held in quarantine until their final release, after which they shall be stored as usable stock under conditions established by the manufacturer.

14.30. The evaluation of finished products and the documentation necessary for release of a product for sale are described.

14.31. Rejected materials and products shall be clearly marked and stored separately in restricted areas. They shall either be returned to the suppliers or, where appropriate, reprocessed or destroyed in a timely manner. Whatever action is taken shall be approved by the authorized personnel and recorded.

14.32. The reworking or recovery of rejected products shall be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. A record shall be kept of the reworking or recovery. A reworked batch shall be given a new batch number.

14.33. The introduction of all or part of earlier batches, conforming to the required quality standards, into a batch of the same product at a defined stage of manufacture shall be authorised beforehand. This recovery shall be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf-life. The recovery shall be recorded.

14.34. The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, shall be considered by the QC Department.

14.35. Recalled products shall be identified and stored separately in a secure area until a decision is taken and the decision shall be made as soon as possible.

14.36. Products returned from the market shall be destroyed unless it is certain that their quality is satisfactory; in such cases they may be considered for resale or relabeling, or alternative action taken only after they have been critically assessed by the QC function in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued shall be taken into account in the assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for reissue or reuse. Any action taken shall be appropriately recorded.

14.37. There shall be records for the receipt and preparation of reagents and culture media.

14.38. Reagents made up in the laboratory shall be prepared according to the written procedures and appropriately labelled. The label shall indicate the concentration, standardization factor, shelf-life, the date when re-standardization is due and the storage conditions. The label shall be signed and dated by the person preparing the reagent.

14.39. Both positive and negative controls shall be applied to verify the suitability of culture media each time they are prepared and used. The size of the inoculum used in positive controls shall be appropriate to the sensitivity required.

15. Reference Standards:

15.1. Whenever official reference standards exist, they shall be used.

15.2. Indian Pharmacopoeia reference standards shall be procured from Indian Pharmacopoeia Commission.

15.3. Official reference standards shall only be used for the purpose described in the appropriate monograph.

15.4. Reference standards prepared by the manufacturer shall be tested, released and stored in the same way as official standards. They shall be kept under the responsibility of a designated person in a secure area.

15.5. Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardization.

15.6. Reference standards shall be properly labelled with at least the following information, namely-

(a) Name of the material;

(b) Batch or lot number and control number;

(d) Shelf-life;

(e) Potency; and

(f) Storage conditions.

15.7. All in-house working standards or secondary standards shall be standardized against an official reference standard, when available, initially and at regular intervals thereafter.

15.8. All reference standards shall be stored and used in a manner that will not adversely affect their quality.

16. Waste materials:

16.1. Provision shall be made for the proper and safe storage of waste materials waiting disposal. Toxic substances and flammable materials shall be stored in suitably designed, separate, enclosed cupboards.

16.2. Waste material shall not be allowed to accumulate. It shall be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals.

16.3. The disposal of sewage and effluents (solid, liquid and gas) from the manufacturing area shall be in conformity with the requirements of the guidelines issued by the Environmental Pollution Control Board.

16.4. All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 2016.

16.5. Rodenticides, insecticides, fumigating agents and sanitizing materials shall not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials or finished products.

17. Documentation:

17.1. Principle-Good documentation is an essential part of the quality assurance system and, as such, shall exist for all aspects of good manufacturing practices. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a drug for sale; to ensure the existence of documented evidence, traceability and to provide records and an audit trial that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis.

The design and use of documents depend upon the manufacturer. In some cases, some or all of the documents described in this paragraph may be brought together, but they will usually be separate.

17.2. General-

17.2.1. Documents shall be designed, prepared, reviewed and distributed with care. They shall comply with the relevant Parts of the manufacturing and licences.

17.2.2. Documents shall be approved, signed and dated by the responsible persons. No document shall be changed without authorization and approval.

17.2.3. Documents shall have unambiguous contents; the title, nature and purpose shall be clearly stated. They shall be laid out in an orderly manner and be easy to check. Reproduced documents shall be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

17.2.4. Documents shall be regularly reviewed and kept up to date. When a document has been revised, a system shall exist to prevent inadvertent use of the superseded version. Superseded documents shall be retained for a specific period of time.

17.2.5. Where documents require the entry of data, these entries shall be clear, legible and indelible. Sufficient space shall be provided for such entries.

17.2.6. Any alteration made to a document shall be signed and dated; the alteration shall be done in such a way so as to permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded.

17.2.7. Records shall be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records shall be retained for at least one year after the expiry date of the finished product.

17.2.8. Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed SOPs relating to the system in use shall be available and the accuracy of the records shall be checked. If documentation is handled by electronic data-processing methods, only authorized persons shall be able to enter or modify data in the computer system, and there shall be a record of changes and deletions; access shall be restricted by passwords or other means and the entry of critical data shall be independently checked. Batch records stored electronically shall be protected by back-up transfer on magnetic tape, microfilm, electronic discs, paper printouts or other means. It is particularly important that, during the period of retention, the data are readily available.

17.2.9 The site master file shall be prepared and maintained.

17.3. Documents Required:

17.3.1. Labels-

17.3.1.1. Labels applied to containers, equipment or premises shall be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g., quarantined, accepted, rejected and clean).

17.3.1.2. All finished drugs shall be identified by labelling bearing at least the following information, namely:-

(a) The name of the drugs;

(b) A list of the active ingredients [if applicable, with the International Nonproprietary Names (INN)], showing the amount of each present and a statement of the net contents (e.g., number of dosage units, weight and volume);

(d) The expiry date and date of manufacture in an uncoded form;

(e) Any special storage conditions or handling precautions that may be necessary

(f) Directions for use, and warnings and precautions that may be necessary; and

(g) The name and address of the manufacturer or the company and the person responsible for placing the product on the market.

17.3.1.3. For reference standards, the label or accompanying document or both shall indicate potency or concentration, date of manufacture, expiry date, date the closure if it is first opened, storage conditions and control number, as appropriate.

17.3.2. Specifications and testing procedures

17.3.2.1. Testing procedures described in documents shall be validated in the context of available facilities and equipment before they are adopted for routine testing.

17.3.2.2. There shall be appropriately authorised and dated specifications, including tests on identity, content, purity and quality for starting and packaging materials and for finished products; where appropriate, they shall also be available for intermediate or bulk products. Specifications for water, solvents and reagents (e.g., acids and bases) used in production shall be included.

17.3.2.3. Each specification shall be approved, signed and dated, and maintained by the QC or QA units. Specifications for starting materials, intermediates, bulk, finished products and packaging materials.

17.3.2.4. Periodic revisions of the specifications may be necessary to comply with new editions of the Indian pharmacopoeia or other official pharmacopoeia.

17.3.2.5. Pharmacopoeias, reference standards, reference spectra and other reference materials shall be available in the QC laboratory.

17.3.3. Specifications for starting and packaging materials-

17.3.3.1. Specifications for starting, primary and printed packaging materials shall provide, if applicable, a description of the materials, including—

(a) The designated name (if applicable, the INN) and internal code reference;

(b) The reference, if any, to a pharmacopoeial monograph; and

17.3.3.2. Depending on the company’s practice other data may be added to the specification, namely:-

(a) The supplier and the original producer of the materials;

(b) A specimen of printed materials;

(d) Storage conditions and precautions; and

(e) The maximum period of storage before re-examination.

17.3.3.3. Packaging material shall conform to the specifications and shall be compatible with the material or with the drugs or both it contains. The material shall be examined for compliance with the specification, and for defects as well as for the correctness of identity markings.

17.3.3.4. Documents describing testing procedures shall state the required frequency for reassaying each starting material, as determined by its stability.

17.3.4. Specifications for intermediate and bulk products- Specifications for intermediate and bulk products shall be available. The specifications shall be similar to specifications for starting materials or for finished products, as appropriate.

17.3.5. Specifications for finished products- Specifications for finished products shall include the following, namely:—

(a) The designated name of the product and the code reference, where applicable;

(b) The designated names of the active ingredients (if applicable, with the INNs);

(d) A description of the dosage form and package details;

(e) Directions for sampling and testing or a reference to procedures;

(f) The qualitative and quantitative requirements, with acceptance limits;

(g) The storage conditions and precautions, where applicable; and

(h) The shelf-life.

17.3.6. Master formula records-

17.3.6.1. A formally authorised master formula shall exist for each product and batch size to be manufactured.

17.3.6.2. The master formula records shall include the following, namely:-

(a) The name of the product, with a product reference code relating to its specification;

(b) A description of the dosage form, strength of the product and batch size;

(c) A list of all starting materials to be used (if applicable with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention shall be made of any substance that may disappear in the course of processing);

(d) A statement of the expected final yield with the acceptable limits and of relevant intermediate yields, where applicable;

(e) A statement of the processing location and the principal equipment to be used;

(f) The methods or reference to the methods to be used for preparing and operating the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilizing, use;

(g) Detailed step-wise processing instructions (e.g., checks on materials, pretreatments, sequence for adding materials, mixing times and temperatures);

(h) The instructions for any in-process controls with their limits;

(i) Where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions;

(j) Any special precautions to be observed; and

(k) The hold time permitted for intermediate and in process material.

17.3.7. Packaging instructions- Formally authorised packaging instructions shall exist for each

Product, pack size and type. These shall normally include or make reference to the following, namely:—

(a) The name of the product;

(b) A description of its pharmaceutical form, strength and, where applicable, method of application;

(d) A complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material;

(e) Where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;

(f) Special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations;

(g) A description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and

(h) Details of in-process controls with instructions for sampling and acceptance limits.

17.3.8. Batch Processing or Manufacturing Records-

17.3.8.1. A batch processing record shall be kept for each batch processed. It shall be based on the relevant Parts of the currently approved specifications on the record. The method of preparation of such records shall be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents shall be avoided.)

17.3.8.2. Before any processing begins a check shall be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check shall be recorded.

17.3.8.3. During processing, the following information shall be recorded at the time each action is taken, and after completion of the record shall be dated and signed by the person responsible for the processing operations, namely:-

(a) The name of the product;

(b) The number of the batch being manufactured;

(d) The name of the person responsible for each stage of production;

(e) The initials of the operators of different significant steps of production and, where appropriate, of the persons who checked each of these operations (e.g., weighing);

(f) The batch number or analytical control number or both and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);

(g) Any relevant processing operation or event and the major equipment used;

(h) The hold time permitted for intermediate and in process material;

(i) The in-process controls performed, the initials of the persons carrying them out, and the results obtained;

(j) The amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield; and

(k) Notes on special problems including details, with signed authorization for any deviation from the master formula.

17.3.9. Batch Packaging Records-

17.3.9.1. A batch packaging record shall be kept for each batch or part batch processed. It shall be based on the relevant Parts of the approved packaging instructions and the method of preparing such records shall be designed to avoid errors. (copying or validated computer programmes are recommended. Transcribing from approved documents shall be avoided.)

17.3.9.2. Before any packaging operation begins, checks shall be made that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations and that equipment is clean and suitable for use. These checks shall be recorded.

17.3.9.3. The following information shall be recorded at the time each action is taken, and the date and the person responsible shall be clearly identified by signature or electronic password, namely:-

(a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;

(b) The date and time of packaging operations;

(d) The initials of the operators of the different significant steps;

(e) The checks made for identity and conformity with the packaging instructions, including the results of in-process controls;

(f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product if it is unpacked or a record of returning product that has not been packaged to the storage area;

(g) Whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;

(h) Notes on any special problems, including the details of any deviation from the packaging instructions, with written authorization by an appropriate person; and

(i) The quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

17.3.10. Standard operating procedures and records:

17.3.10.1. Standard Operating Procedures (hereinafter to be referred as SOPs) and associated records of actions taken or, where appropriate, conclusions reached shall be available for the following, namely-

(a) Equipment assembly and validation;

(b) Analytical apparatus and calibration;

(d) Personnel matters including qualifications, training, clothing and hygiene;

(e) Environmental monitoring;

(f) Pest control;

(g) Complaints;

(h) Recalls; and

(i) Returns.

17.3.10.2. There shall be SOPs and records for the receipt of each delivery of starting material and primary and printed packaging material.

17.3.10.3. The records of the receipts shall include the following, namely-

(a) The name of the material on the delivery note and the containers;

(b) The “in-house” name or code or both of material, if different from clause

(d) The supplier’s name and, if possible, manufacturer’s name;

(e) The manufacturer’s batch or reference number;

(f) The total quantity and number of containers received;

(g) The batch number assigned after receipt; and

(h) Any relevant comment (e.g. state of the containers).

17.3.10.4. There shall be SOPs for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

17.3.10.5. SOPs shall be available for each instrument and piece of equipment (e.g., use, calibration, cleaning and maintenance) and placed in close proximity to the equipment.

17.3.10.6. There shall be SOPs for sampling, which specify the persons authorised to take samples.

17.3.10.7. The sampling instructions shall include-

(a) The method of sampling and the sampling plan;

(b) The equipment to be used;

(d) The amount of samples to be taken;

(e) Instructions for any required sub-division of the sample;

(f) The type of sample containers to be used, and whether they are for aseptic sampling or for normal sampling and labelling; and

(g) Any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material.

17.3.10.8. There shall be a SOPs describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number.

17.3.10.9. The SOPs for batch numbering that are applied to the processing stage and to the respective packaging stage shall be related to each other.

17.3.10.10. The SOPs for batch numbering shall ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing.

17.3.10.11. Batch-number allocation shall be immediately recorded, e.g. in a logbook. The record shall include at least the date of allocation, product identity and size of batch.

17.3.10.12. There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.

17.3.10.13. Analysis records shall include at least the following data, namely-

(a) The name of the material or product and, where applicable, dosage form;

(b) The batch number and, where appropriate, the manufacturer and supplier;

(d) Test results, including observations and calculations, and reference to any specifications (limits);

(e) Date and reference number of testing;

(f) The initials of the persons who performed the testing;

(g) The date and initials of the persons who verified the testing and the calculations, where appropriate; and

(h) A clear statement of release or rejection (or other status decision) and the dated signature of the designated person.

17.3.10.14. Written release and rejection procedures shall be available for materials and products and in particular for the release for sale of the finished product by an authorized person.

17.3.10.15. Records shall be maintained regarding the distribution of each batch of a product in order, for example, to facilitate the recall of the batch, if necessary.

17.3.10.16. Records shall be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning or repair operations, including dates and the identity of the people who carried out these operations.

17.3.10.17. The use of major and critical equipment and the areas where products have been processed shall be appropriately recorded in chronological order.

17.3.10.18. There shall be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned and such written procedures shall be followed.

18. Good Practices in Production:

18.1. Principle- Production operations must follow clearly defined procedures in accordance with Manufacturing and licences, with the objective of obtaining products of the requisite quality.

18.2. General-

18.2.1. All handling of materials and products, such as receipt and cleaning, quarantine, sampling, Storage, labelling, dispensing, processing, packaging and distribution shall be done in accordance with written procedures or instructions and, where necessary, recorded.

18.2.2. Deviation from instructions or procedures shall be avoided as far as possible. If deviations occur, they shall be in accordance with an approved procedure. The authorization of the deviation shall be approved in writing by a designated person, with the involvement of the QC Department, when appropriate.

18.2.3. Checks on yields and reconciliation of quantities shall be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

18.2.4. Operations on different products shall not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix up or cross-contamination.

18.2.5. At all times during processing, all materials, bulk containers, major items of equipment, and, where appropriate, the rooms and packaging lines being used, shall be labelled or otherwise

identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication shall also mention the stage of production. In some cases, it may be useful to also record the name of the previous product that has been processed.

18.2.6. Access to production premises shall be restricted to authorized personnel.

18.2.7. Non-medicinal products shall not be produced in areas or with equipment destined for the Production of pharmaceutical products.

18.2.8. In-process controls are usually performed within the production area. The performance of such in-process controls shall not have any negative effect on the quality of the product or another Product (e.g., cross-contamination or mix up).

18.3. Prevention of cross-contamination and bacterial contamination during production-

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

18.3.2. Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, particles, vapours, sprays or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators’ clothing, skin, etc.

The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses or over a long time or both. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authorities.

18.3.3. Cross-contamination shall be avoided by taking appropriate technical or organizational measures, namely:-

(a) Carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, cytotoxic, sex hormones, spore forming, 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;

(d) Minimizing the risk of contamination caused by recirculation or re-entry 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; and

(i) Using cleanliness status labels on equipment.

18.3.4. 1Measures to prevent cross-contamination and their effectiveness shall be checked periodically according to SOPs.

18.3.5. Production areas where susceptible products are processed shall undergo periodic environmental monitoring (e.g., for microbiological and particulate matter, where appropriate).

18.4. Processing operations-

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

18.4.2. Any necessary in-process controls and environmental controls shall be carried out and recorded.

18.4.3. Means shall be instituted of indicating failures of equipment or of services (e.g., water and gas) to equipment. Defective equipment shall be withdrawn from use until the defect has been rectified. After use, production equipment shall 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.

18.4.4. Time limits for storage of process materials and equipment, after cleaning and before use, shall be stated and based on relevant data.

18.4.5. Containers for filling shall be cleaned before filling. Attention shall be given for avoiding and removing any contaminants such as glass fragments and metal particles.

18.4.6. Any significant deviation from the expected yield shall be recorded and investigated.

18.4.7. Checks shall be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another area are connected in the correct manner.

18.4.8. Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes shall be sanitized and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

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

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

18.5. Packaging operations:

18.5.1. When the programme for packaging operations is being set up, particular attention shall be given to minimising the risk of cross-contamination, mix ups or substitutions. Different products shall not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance.

18.5.2. Before packaging operations are begun, steps shall 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 shall be performed according to an appropriate procedure and checklist and shall be recorded.

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

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

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

18.5.6. Special care shall be taken when cut labels are used and when overprinting is carried out offline and in hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mix ups. Online verification of all labels by automated electronic means can be helpful in preventing mix ups, but checks shall be made to ensure that any electronic code readers, label counters or similar devices are operating correctly. When labels are attached manually, in-process control checks shall be performed more frequently.

18.5.7. Printed and embossed information on packaging materials shall be distinct and resistant to fading or erasing.

18.5.8.1. Regular online control of the product during packaging shall include at a minimum checks on—

(a) The general appearance of the packages;

(b) Whether the packages are complete;

(d) Whether any overprinting is correct; and

(e) The correct functioning of line monitors.

18.5.8.2. Samples taken away from the packaging line shall not be returned.

18.5.9. Products that have been involved in an unusual event during packaging shall be reintroduced into the process only after special inspection, investigation and approval by the authorized personnel. A detailed record shall be kept of this operation.

18.5.10. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced shall be investigated, satisfactorily accounted for and recorded before release.

18.5.11. Upon completion of a packaging operation, any unused batch-coded packaging materials shall be destroyed and the destruction shall be recorded. A documented procedure requiring checks to be performed before returning unused materials shall be followed, if uncoded printed materials are returned back to the stock.

18.5.12. Production records shall be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet production specifications shall be thoroughly investigated. The investigation shall, 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 shall be made and shall include the conclusion and follow-up action.

19. Good Practices in Quality Control:

19.1. Quality control is the part of good manufacturing practices concerned with sampling, specifications and testing and with the organization and documentation which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be compliant with the requirements. QC is not confined to laboratory operations, but may be involved in many decisions concerning the quality of the product.

19.2. The independence of QC from production is considered fundamental.

19.3. Each manufacturer shall have a QC function. The QC function shall be independent of other Departments and under the authority of a person with appropriate qualifications and experience. Adequate resources must be available to ensure that all the QC arrangements are effectively and reliably carried out. 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 good manufacturing practices purposes;

(b) samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved by the QC Department;

(d) Records must be made (manually or by recording instruments or both) demonstrating that all the required sampling, inspecting and testing procedures have actually been carried out and that any deviations have been fully recorded and investigated;

(e) The finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the licence; the ingredients must be of the required purity, in their proper container and correctly labelled;

(f) Records must be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures;

(g) Sufficient samples of starting materials and products must be retained to permit future examination of the product, if necessary; the retained product must be kept for the appropriate time in its final pack unless the pack is exceptionally large, in which case one that is equivalent to the marketed packaging system may be used.

19.4 Other QC responsibilities include the following, namely:-

(a) Establishing, validating and implementing all QC procedures;

(b) Evaluating, maintaining and storing reference standards for substances;

(d) Ensuring that the stability of the active pharmaceutical ingredients and products are monitored;

(e) Participating in the investigation of complaints related to the quality of the product;

(f) Participating in environmental monitoring; and

(g) Participation in quality risk management programme.

19.4.1. These activities shall be carried out in accordance with written procedures and, where necessary, recorded.

19.5. Quality control personnel shall have access to the production areas for sampling and investigation as appropriate.

19.6. Control of starting materials and intermediate, bulk and finished products-

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

19.6.2. Samples shall be representative of the batches of material from which they are taken in accordance with the approved written procedure.

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

19.6.4. Care shall 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 shall be clean. Hazardous or potent materials may require special precautions.

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

19.6.6. Each sample container shall bear a label indicating-

(a) The name of the sampled material;

(b) The batch or lot number;

(d) The number of the sample;

(e) The signature of the person who has taken the sample; and

(f) The date of sampling.

19.6.7. Out-of-specification results obtained during testing of materials or products shall be investigated in accordance with an approved procedure and record shall be maintained.

19.7. Test requirements-

19.7.1. Before releasing a starting or packaging material for use, the QC in-charge shall ensure that the materials have been tested for conformity with specifications for identity, strength, purity and other quality parameters.

19.7.2. An identity test shall be conducted on a sample from each container of starting material. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled.

19.7.2.1. The above validation shall take account of at least the following aspects, namely:-

(a) The nature and status of the manufacturer and of the supplier and their understanding of the good manufacturing practices requirements;

(b) The QA system of the manufacturer of the starting material;

(d) The nature of the starting material and the medicinal products in which it will be used.

19.7.2.2. Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following, namely-

(a) Starting materials coming from a single product manufacturer or plant; or

(b) starting materials coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body.

19.7.2.3. It is improbable that such a procedure could be satisfactorily validated for either-

(a) Starting materials supplied by intermediaries, such as brokers, where the source of manufacture is unknown or not audited; or

(b) Starting materials for use in parenteral products.

19.7.3. Each batch (lot) of printed packaging materials shall be examined following its receipt.

19.7.4. In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from

the supplier, provided that the manufacturer establishes the reliability of the supplier’s analysis through appropriate periodic validation of the supplier’s test results and through on-site audits of the supplier’s capabilities. Certificates must be originals and not photocopies or otherwise have their authenticity assured. Certificates must contain at least the following information, namely:—

(a) Identification (name and address) of the issuing supplier;

(b) Signature of the competent official and statement of his or her qualifications;

(d) The batch number of the material tested;

(e) The specifications and methods used;

(f) The test results obtained; and

(g) The date of testing.

19.7.5. In-process control records shall be maintained and form part of the batch records.

19.7.6. For each batch of drugs, there shall be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to its release.

19.7.7. Products failing to meet the established specifications or any other relevant quality criteria shall be rejected.

19.8. Batch record review:

19.8.1. Quality control records shall be reviewed as part of the approval process of batch release before transfer to the authorised person. Any divergence or failure of a batch to meet its specifications shall be thoroughly investigated. The investigation shall, 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 shall be made and shall include the conclusion and follow-up action.

19.8.2. Retention samples from each batch of finished product shall be kept for at least one year after the expiry date. Finished products shall usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials shall 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) shall be retained for a minimum of two years, if their stability allows. Retention samples of materials and products shall be of a size sufficient to permit at least two full reexaminations.

19.9. Stability studies-

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

19.9.2. QC shall establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions.

19.9.3. A written programme for on-going stability determination shall be developed and implemented to include elements such as —

(a) A complete description of the drug 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;

(d) The testing schedule for each drug;

(e) Provision for special storage conditions;

(f) Provision for adequate sample retention; and

(g) A summary of all the data generated, including the evaluation and the conclusion of the study.

19.9.4. Stability shall be determined prior to marketing and following any significant changes, for example, in processes, equipment or packaging materials.

20. Computerized systems:

20.1. GMP-related computerized systems shall be validated. The depth and scope of validation depends on the diversity, complexity and criticality of the computerized application.

20.2. Appropriate installation qualification and operational qualification shall demonstrate the suitability of computer hardware and software to perform assigned tasks.

20.3. Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at the time of installation, a retrospective validation could be conducted, if appropriate documentation is available.

20.4. Computerized systems shall have sufficient controls to prevent unauthorized access or changes to data. There shall be controls to prevent omissions in data (e.g., the system being turned off and data not captured). There shall be a record of any data change made, the previous entry, the person who made the change and when the change was made.

20.5. Written procedures shall be available for the operation and maintenance of computerized systems.

20.6. Where critical data are being entered manually, there shall be an additional check on the accuracy of the data entered. This can be done by a second operator or by the system itself.

20.7. Incidents related to computerized systems that could affect the quality of products or the reliability of records or test results shall be recorded and investigated.

20.8. Changes to the computerized system shall be made according to a change procedure and shall be formally authorized, documented and tested. Records shall be kept of all changes, including modifications and enhancements made to the hardware, software and any other critical component of the system. These records shall demonstrate that the system is maintained in a validated state.

20.9. A back-up system shall be provided so that there is no permanent loss of records due to system breakdown or failure. Means of ensuring data protection shall be established for all computerized systems.

20.10. Data may be recorded by other means in addition to the computer system

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