A Standard Operating Procedure SOP for cGMP Internal Audit / Self Inspection in the pharmaceutical industry is vital for ensuring compliance with Good Manufacturing Practice (cGMP) guidelines and maintaining a high level of quality and safety in the manufacturing process. Below is a general outline for creating an SOP for cGMP Internal Audit or Self-Inspection
SOP for cGMP Internal Audit / Self Inspection Scope
- QA Head is responsible for planning, team selection, and execution of audit / inspection and closing of report.
- It is the responsibility of QA department to schedule cGMP Internal Audits on biannual basis (twice a year)
- It is the responsibility of Internal Auditors (QA and other trained individuals) to conduct audit as planned, prepare report and do follow up inspection to evaluate corrective & preventive action.
- It is the responsibility of the department to provide full access to its facilities for Self-Inspection
- It is responsibility of the audited department to respond to audit report within 15 days of the receipt of inspection report on what corrective action is to be taken.
- It is the responsibility of QA Manager to make certain that this SOP is followed in its entirety.
- It is the responsibility of Assistant QA Manager or Designee to review this SOP.
- It is the responsibility of QA Head or Designee to approve this SOP.
- It is the responsibility of Director Technical / Operations to authorize this SOP.
Definitions & Abbreviations
- Internal Audit: An activity done by the independent trained personnel according to the pre-determined frequency to monitor the implementation of cGMP and to propose any necessary corrective measures. Records of such inspection and any subsequent corrective action shall be maintained.
- Self Inspection: A systematic inspection program done by the responsible personnel themselves according to pre-determined frequency to detect any short comings in the implementation of cGMP and to recommend necessary corrective actions.
- Audit Team: Auditing the facility and to prepare audit report comprising of recommendations and corrective action necessary for respective departments, that must consist of a lead auditor, co-auditor and trainee auditor.
- Auditor: A person who has the technical qualification or is trained or the experience to perform audits.
- Auditee: A department / person to be audited and to assist with the auditors at the time of audit / inspection and comply with the Non-conformances reported by the Auditors.
- Lead Auditor: A person who leads the team to execute the Inspection / audit on the plan date and prepare the report.
- Co-Auditor: A person to support the lead auditor for execution of inspection and report preparation.
- SOP: Standard Operating Procedure.
- QM: Quality Management.
- NCR: Non-Conformance Report.
- cGMP: Current Good Manufacturing Practices.
- QA: Quality Assurance
- QC: Quality Control
- PR: Production
- WH: Warehouse
- PU: Procurement
- EG: Engineering
- IT: Information Technology
SOP for cGMP Internal Audit / Self Inspection Procedures
- Internal auditors are selected based on their training and experience in implementation of GMP.
- The auditor team comprised of lead auditor, co-auditor and trainee auditor, selection based on his / her training, expertise and experience. As an alternative, the internal audit can be done by an individual competent auditor as selected by QA.
- While selecting a team member for audit team, the QA Head ensures that the member is not from the same department for which audit is to be carried out.
Planning and Scheduling Audit
- Audit all departments on biannual basis (twice a year) as per schedule.
- QA prepares schedule of audits and communicate it to the department in advance.
- In case of schedule change, the new schedule is communicated to auditor(s) and the department.
- Conduct audit during normal working hours
- Auditors must have a general audit plan including the following:
- Previous audit report, if the department have been audited before
- Audit Checklist (if required)
- Asking open-ended questions
- Listening and understanding
- Restating responses
- Allowing time for responses
- Showing flexibility and a constructive attitude
- Choosing proper vocabulary
- Internal Audit Report must be prepared within two days from the date of inspection and circulated to the concerned department head and record the same in the Internal Audit / Self Inspection Log Book.
- Respective departmental heads are responsible for preparing the Compliance Report for the deficiencies reported within a time frame of 15 days from the receipt of audit report and submit to QA.
- The date of receipt of compliance report is recorded in Internal Audit / Self Inspection Log Book (Annexure A).
- Following completion of an audit, an audit report is prepared by the auditors highlighting the state of GMP non-conformances. The non-conformances is classified into the following classes:
Audit Follows Up
- Conduct audit follows up to assess the state of cGMP non-conformance(s) within target dates given by department.
- Verify corrective actions have been implemented. If not write up a new non-conformance report with new target date.
- Keep all GMP non-conformance reports and related document in QA for five years.
Result SOP for cGMP Internal Audit / Self Inspection
- The result of audit report is presented at the management board meeting.
- Internal audit’s finding, report, follow up are confidential information and is intended for internal use and not subject to external use.
- Self-Inspection is done at departmental level i.e. representative of department performs inspection of all the documents and activities done by the department.
- The representatives are nominated as auditors by the Department Head and have direct reporting to department head.
- An inspection report is prepared, and corrective and preventive action is determined, filed and implemented.
- The representatives perform the audit of previous month document and activities.
- All self-inspection documentations are archived in QA department.
- Keep all the self-inspection observation reports confidential as an internal system for improvement which is strictly prohibited for external reviews.
- The frequency of self-inspection is scheduled after every 3 Months or when required.
- Self-Inspection Report must be prepared within two days from the date of inspection and circulated to the concerned department head and record the same in the Internal Audit / Self Inspection Log Book.
- Respective departmental heads are responsible for preparing the Compliance Report for the deficiencies reported within a time frame of 7 days from the receipt of self-inspection report and submit to QA.
- The date of receipt of compliance report is recorded in Internal Audit / Self Inspection Log Book (Annexure A).
- In case of inspection or directions from regulatory agency, unscheduled inspections can be carried out at the direction of Head QA.
- In case of any critical market complaint, product recall related to quality issue or critical GMP non-conformance e.g. Product mix ups, batch failure, self-inspection / internal audit can be initiated immediately in the respective areas / systems before the approved schedule.
- Update audit checklist of cGMP if required.
Attached Documents (Forms / Annexure)
- Internal Audit / Self Inspection Log Book (Annexure A)
- cGMP Audit Summary Report (QA/FRM/01/0014)
- cGMP Non – Conformance Report (QA/FRM/02/0014)
- cGMP Internal Auditor List (QA/FRM/03/0014)
- cGMP Internal Audit Schedule (QA/FRM/04/0014)
- cGMP Internal Audit Check List (QA/FRM/05/0014)
Reference & Linked Documents
- EU Guidance on Good Manufacturing Practices
- Good Manufacturing Practices (GMPs) For Manufacturers. Schedule B-II Under the Drugs (Licensing, Registering & Advertising) Rules 1976, Framed Under the Drugs Act, 1976
- ICH Harmonised Tripartite Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredient.
Internal Audit / Self Inspection Log Book
cGMP Audit Checklist
|To be filled by Auditor
|Section 1: Quality Assurance System
|(a) Drugs are designed and developed as per requirements of good manufacturing practices.
|(b) Production and control operations are clearly specified in a written form and good manufacturing practices requirements are adopted and followed.
|(c) Managerial responsibilities are clearly specified in job descriptions.
|(d) Arrangements are made for manufacture, supply and use of the correct starting / packaging materials.
|(e) All necessary controls on starting materials, intermediate products, and bulk products and other in process controls calibrations and validations are carried out.
|(f) The finished products are correctly processed and checked, according to the defined procedures.
|(g) Finished drugs are not sold or supplied before the authorized person(s) has certified that each production batch has been produced and controlled in accordance with the requirements of the good manufacturing practices and the relevant rules made under the Act relevant to the production, control and release of drugs as well as of conditions of registration.
|(h) Satisfactory arrangements exist to store in appropriate storage conditions.
|(i) Procedure for self inspection and or quality audit exists and documented.
|(j) Written Standard Operating Procedure available according to which complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products and to prevent recurrence and that system is followed.
|Section 2: Quality control
|Quality control department exists which is independent of other departments and under the authority of a person with the required qualifications and experience and with adequate facilities.
|(a) During the period of validity of license, adequate facilities, trained personnel and approved procedures are available for sampling, inspecting, testing starting materials, packaging materials, 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 are taken by methods, and personnel approved of by the quality control department.
|(c) Testing methods are validated;
|(d) Records are made that all the required sampling, inspecting and testing procedures have actually been carried out and that any deviation has been fully recorded and investigated.
|(e) The finished products contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorization.
|(f) Records are made of the results of inspecting and testing materials and intermediate, bulk and finished products against specifications and product assessment.
|(g) No batch of product is released for sale prior to certification by the authorized person(s) that it is in accordance with the requirement of the rules.
|(h) Sufficient samples of starting materials and products are retained to permit future examination of the product.
|(i) All quality control procedures are established, validated and implemented; the reference standards for substances are evaluated maintained, and stored; correct labeling of containers of materials and products is ensured; the stability of the active pharmaceutical ingredients and products is monitored.
|(j) Complaints related to the quality of the product are investigated.
|(k) All these operations shall be carried out in accordance with written procedures.
|General: All tests and analysis conducted shall be in accordance with the instructions given in the relevant written test procedures. The result shall be checked by the supervisor before the material or product is released or rejected.
|Sampling: The samples shall;
|(a) be representative of the batches of material from which they are taken and in accordance with the approved written procedure.
|(b) be taken in a manner so as to avoid contamination or other adverse effect on quality.
|(c) be taken with care to guard against contamination or mix-up. All sampling equipment that comes into contact with the material shall be clean.
|(d) be taken with equipment which shall be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment.
|Test requirement for starting and packaging materials:
|(a) Test before use: Before releasing a starting or packaging material for use, the quality control manager ensure that the materials have been tested for conformity with specifications for identity, strength, purity, and other quality parameters.
|(b) Identity from each container: An identity test shall be conducted on a sample from each container of starting material.
|(c) Examination of each batch: Each batch (lot) of printed packaging materials shall be examined following receipt.
|Test requirement for in-process control:
|(a) Records of testing: In process control records shall be maintained and form a part of the batch records.
|Test requirements for finished products:
|(a) Testing each batch: For each batch of drug product, there shall be an appropriate laboratory determination of satisfactory conformity to its finished product specifications prior to release.
|(b) Rejection of failed products: Product failing to meet the established specifications or any other relevant quality criteria may be revalidated and shall be rejected if they do not qualify revalidation protocols.
|(c) Reprocessing: Reprocessing may be performed, if feasible, but the reprocessed product shall meet all specifications and other quality criteria prior to its acceptance and release.
|Production record and batch review;
|(a) Review of Records: Production and control records shall be reviewed.
|(b) Retention of Samples: Retention samples from each batch of finished product shall be kept for at least one year after the expiry date.
|(i) The quality control department shall;
|(a) Evaluate the quality and stability of finished pharmaceutical products and, of starting materials and intermediate products.
|(b) Establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions.
|(ii) A written program for ongoing stability determination shall be developed and implemented to include elements.
|(iii) Stability of the finished product shall be evaluated and documented prior to marketing.
|General: The management shall appoint a self inspection team. 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 program. Self inspections shall be performed routinely.
|Items for self-inspection: Written instructions for self-inspection shall be established to provide a minimum and uniform standard of requirements.
|Frequency of self-inspection: it shall be at least once every year.
|Self-inspection report: A report shall be made at the completion of self-inspection which shall include;(a) self-inspection results;(b) evaluation and conclusions; and(c) recommended corrective actions.
|Audit by independent specialist: Quality audit shall be conducted which consists of an examination and assessment of all or part of a quality system.
|Supplier’s audits: The quality control department shall have responsibility together with other relevant departments for approving suppliers.
|Review of complaints: All complaints must be carefully reviewed according to written procedures.
|Person authorized: A person responsible for handling the complaints.
|Written procedures: 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.
|Recording defects and investigation: Any complaint concerning a product defect shall be recorded with all the original details and thoroughly investigated.
|Investigation: If a product defect is discovered or suspected in a batch, consideration shall be given to whether other batches shall be checked in order to determine whether they are also affected.
|Follow-up action: Where necessary, appropriate follow-up section, possibly including product recall, shall be taken after investigation and evaluation of the complaint.
|Recording measures: All the decisions and measures taken as a result of a complaint shall be recorded and referenced to the corresponding batch records.
|Review for recurring problems: Complaint record shall be regularly reviewed for any indication of specific or recurring problems that require attention.
|System: There shall be a system to promptly and effectively recall from the market the products known or suspected to be defective.
|Authorized person: A person responsible for the execution and coordination of recalls shall be designated.
|Written procedure: There shall be established written procedures, regularly checked and updated for the organization of any recall activity.
|Recall with promptness: All competent authorities to whom a given product may have been distributed shall be promptly informed of any intention to recall the product.
|Distribution records: The distribution records shall be readily available to the person(s) responsible for recall.
|Recording of progress: The progress of the recall process shall be recorded and a final report issued, including reconciliation between the delivered and recovered quantities of the products.
|Evaluation: The effectiveness of the arrangements for recalls shall be evaluated from time to time.
|Storage of recalled drugs: An instruction shall be included to store recalled products in a secure segregated area while their fate is decided.
|Section 3: Personnel
|General: The licensee shall provide;
|(a) Sufficient qualified personnel (at least one technical person for each section) to fulfill all its responsibilities required under the rules.
|(b) Organization chart.
|Written duties: All responsible staff shall have their specific duties recorded in written descriptions.
|Good manufacturing practices awareness: All personnel shall be aware of the principles of good manufacturing practices that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.
|Prohibition of unauthorized persons: Steps shall be taken to prevent unauthorized people from entering production, storage, and quality control areas and personnel who do not work in these areas shall not use them as a passageway.
|Duties of head of departments: The head of the production and quality control department may have shared, or jointly exercised the following responsibilities relating to quality, namely:
|(a) The authorization of written procedures and other documents, including amendments.
|(b) The monitoring and control of the manufacturing environment.
|(c) Plant hygiene.
|(d) Process validation and calibration of analytical apparatus.
|(e) Training, including the application and principles of quality assurance.
|(f) The approval and monitoring of suppliers of materials.
|(g) The approval and monitoring of contract manufacturers.
|(h) The designation and monitoring of storage conditions for materials and products.
|(i) The retention of records.
|(j) The monitoring of compliance with good manufacturing practices and requirements
|(k) The inspection, investigation, and taking of samples in order to monitor factors that may affect product quality.
|Duties of production incharge: The head of the production department may have the following responsibilities, namely;
|(a) To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality.
|(b) To approve the instructions relating to production operations including the in-process controls, and to ensure their strict implementation.
|(c) To ensure that the production records re-evaluated and signed by a designated person before they are made available to the quality control department.
|(d) To check the maintenance of the department, premises, and equipment.
|(e) To ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available.
|(f) To ensure that the required initial and continuing training of production personnel is carried out and adapted according to need.
|Duties of Quality Control Incharge: The head of the quality control department shall have the following responsibilities, namely;
|(a) To approve or reject starting materials, packaging materials, and intermediate, bulk, and finished products.
|(b) To evaluate batch records.
|(c) To ensure that all necessary testing is carried out.
|(d) To approve sampling instructions, specifications, test methods, and other quality control 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 validation, including those of analytical procedures and calibrations of control equipment are done.
|(h) To ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need.
|Written programme: The training shall be provided in accordance with a written program for all the personnel whose duties require them to work in the production areas, as the case may be, in the control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product.
|Training appropriate to duties: 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, continuing training shall also be given, and its practical effectiveness shall be periodically assessed, training programs shall be available, approved by the head of either production or quality control, as appropriate, and training records shall be kept.
|Specific training: Personnel working in areas where contamination is a hazard, such as clean areas or areas where highly active, toxic, infectious, or sensitizing materials are handled shall be given specific training.
|Understanding concepts: The concept of quality assurance and all the measures capable of improving its understanding and implementation shall be fully discussed during the training sessions.
|Visitors or untrained personnel discouraged: Visitors or untrained personnel shall be discouraged entry into the production and quality control areas.
|Health Examination: All personnel prior to and during employment as may be appropriate, shall undergo health examinations and personnel conducting visual inspections shall also undergo periodic eye examinations.
|Practices in personal hygiene: 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, personnel shall be instructed particularly to wash their hands before entering production areas, and signs to this effect shall be pasted and instructions observed.
|Illness: Any person down 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 drug products until the condition is no longer judged to be a risk.
|Reporting health problems: 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.
|Avoiding direct contact with materials: Direct contact shall be avoided between the operator’s hands and starting materials, primary packaging materials, and intermediate or bulk product.
|Appropriate clothing and covering: To ensure protection of the product from contamination, personnel shall war clean body coverings appropriate to the duties they perform, including appropriate hair cover, and used clothes, if re-usable, shall be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized.
|Foods and drinks prohibited: Smoking, eating, drinking, chewing and keeping plants, food, drink, smoking material, and personal medicine shall not be permitted in production, laboratory, and storage areas or in any other areas where they might adversely influence product quality.
|Section 4: Production
|General responsibility of licensee: The licensee shall follow Good Manufacturing Practices in production of drugs under which it shall be ensured that;
|(a) All manufacturing processes which shall be defined are systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications.
|(b) Critical steps of manufacturing processes and any significant change made to the processes are validated.
|(c) All necessary facilities are continued to be made available including;
(i) appropriately qualified and trained personnel
(ii) adequate premises and space
(iii) suitable equipment and services
(iv) correct materials, containers, and labels
(v) approved procedures and instructions
(vi) suitable storage and transport
(vii) adequate personnel, laboratories and equipment for in-process controls under the responsibility ofthe production management.
|(d) Instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided and followed in letter and spirit.
|(e) Operators receive training and refresher courses at regular intervals to carry out procedures correctly, and records of such training are maintained.
|(f) Records are made, manually and or by recording instruments, during manufacture to show that all the steps required by the defined producers and instructions have in fact been taken and that the quantity and quality of the product are as expected, and any significant deviations are fully recorded and investigated.
|(g) Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form.
|(h) The proper storage and distribution of the products minimizes any risk to their quality.
|(i) The written system to recall any batch of product from sale or supply is followed whenever a recall is necessitated.
|Section 5: Material
|Quarantine: All incoming materials and finished products shall be quarantined immediately after receipt or processing, until they are released for use or distribution.
|Appropriate storage: All materials and products shall be stored under the appropriate conditions established by the manufacturer and in an orderly manner to permit batch segregation and stock rotation by a first-in, first-out rule.
|Purchase: The purchase of starting materials is an important operation that must involve staff who have a particular and thorough knowledge of the products and suppliers and a pharmacist with some experience of production may be preferred.
|Purchase from producer or established supplies: Staring materials shall be purchased directly from the producer or only form established suppliers.
|Checking of containers: For each consignment, the containers shall be checked for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier’s labels and, containers shall be cleaned where necessary and labeled, if required, with the prescribed data.
|Damaged container: 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.
|Delivery from different batches: If a delivery of material is made up of different batches, each batch shall be considered as separate for sampling, testing and release.
|Labeling: Starting materials in the storage area shall be appropriately labeled, and 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(s) given by the supplier and on receipt by the manufacturer, if any.(c) Where appropriate, the status of the contents such as on quarantine, on test, released, rejected returned, and recalled.(d) Where appropriate an expiry date or a date beyond which retesting is necessary. When fully computerized storage systems are used appropriate system shall be developed for the identification of above referred information.
|Identity of contents: There shall be appropriate procedures or measures to ensure the identity of the contents of each container of staring material, but bulk containers form which samples have been drawn shall be identified.
|Released materials to be used: Only starting materials released by or quality control department and within their shelf-life shall be used.
|Procedure to ensure that the correct materials are accurately weighted or measured into clean and properly labeled containers.
|Checking: Each dispensed material and its weight or volume shall be independently checked and the check recorded.
|Labeling: Materials dispensed for each batch of the final product shall be kept together and conspicuously labeled as such.
|Purchase: The purchase, handling and control of primary and printed packaging materials shall be as for starting materials.
|Printed materials: Particular attention shall be paid to printed packaging materials which shall be stored in secure conditions so as to exclude the possibility of unauthorized access, cut labels, and other loose printed materials shall be stored and transported in separate closed containers so as to avoid mix-ups and packaging materials shall be used for use only by designated personnel following an approved and documented procedure.
|Reference numbers: Each delivery or batch of printed or primary packaging material shall be given a specific reference number or identification mark.
|Obsolete materials: Outdated or obsolete primary packaging material or printed packaging material shall be destroyed and its disposal should be recorded.
|Checking before delivery: 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.
|Intermediate and Bulk Products:
|Storage: Intermediate and bulk products shall be kept under appropriate conditions.
|Handling: Intermediate and bulk products purchased as such shall be handled on receipt as though they were starting materials.
|Finished Pharmaceutical Products:
|Quarantine: Finished pharmaceutical products shall be held in quarantine until their final release, and thereafter they shall be stored as usable stock under conditions established by the manufacturer.
|Release: The evaluation of finished products and the documentation necessary for release of a product for sale, as per requirement of these rules, shall be followed.
|Rejected and Recovered Materials:
|Storage and disposal: Rejected materials and products shall be clearly marked as such and stored separately in restricted areas, and they shall either be returned to the suppliers, or, where appropriate, reprocessed or destroyed and then action shall be approved by authorized personnel and recorded.
|Reprocessing: The reprocessing of rejected products shall be exceptional, it is permitted only if the quality of the final product is not affect, if the specifications are met, and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved and record shall be kept of the reprocessing and a reprocessed batch shall be given a new batch number.
|Batch recovery: The introduction of all or part of earlier batches, conforming to the required quality, into a batch of the same product at a defined stage of manufacture shall be authorized 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 and the recovery shall be recorded.
|Additional testing of reprocessed materials: The need for additional testing of any finished product that has been reprocessed, or into which a recovered product has been incorporated, shall be considered by the quality control department.
|Recalled and Returned Products:
|Recalled products: Recalled products shall be identified, clearly marked as such and stored separately in a secure area until a decision is taken on their fate.
|Returned goods: Products returned from the market shall be destroyed unless it is certain that their quality is satisfactory, they may be considered for resale, relabeling, or bulking with a subsequent batch only after they have been critically assessed by the quality control department 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 all be taken into account in this assessment, where any doubt arises over the quality of the product, it shall not be considered suitable for reissue or re-use, although basic chemical reprocessing to recover the active ingredient may be possible, and any action taken shall be appropriately recorded.
|Reagents and Culture Media:
|All reagents and culture media shall be recorded upon receipt or preparation.
|Reagents made up in the laboratory shall be prepared according to written procedures and appropriately labeled, the label shall indicate the concentration, standardization factor, shelf-life, the date when re-standardization is due, and the storage conditions and the label shall be signed and dated by the person preparing the reagent.
|Both positive and negative controls shall be applied to verify the stability of culture media and the size of the inoculums used in positive controls shall be appropriate to the sensitivity required.
|Testing of prepared reference standard: Reference standards may be available in the form of official reference standards and reference standards prepared by the producer shall be tested, released, and then stored in the same way as official standards, and they shall be kept under the responsibility of a designated person in a secured area.
|Use: Official reference standards shall be used only for the purpose described in the appropriate testing method submitted for registration purposes.
|Working standards: Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardization, and all in-house reference standards shall be based on official reference standards, when available.
|Storage: All reference standards shall be stored and used in a manner that will not adversely affect their quality.
|Storage: Provision shall be made for the proper and safe storage of waste materials awaiting disposal, and toxic substances and flammable materials shall be stored in suitably designed and separate enclosed cupboards.
|Disposal: Waste material shall not be allowed to accumulate, and 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.
|Effluent Control: There shall be a effluent control system.
|Rodenticides, insecticides, fumigating agents and sanitizing materials shall not be permitted to contaminate equipment, starting materials, packaging, materials, in-process materials, or finished products.
|General: Production operations must follow clearly defined procedures with the objective of obtaining products of the requisite quality.
|Material handling: All handling of materials and products such as receipt and quarantine, sampling, storage, labeling, dispensing, processing, packaging, and distribution shall be done in accordance with written procedures or instructions and, where necessary, recorded.
|Avoiding deviation: Any deviation from instructions or procedures shall be avoided as far as possible and if deviations occur, they shall be approved in writing by a designated person, with the involvement of the quality control department.
|Yield checks: Check on yields and re-conciliation of quantities shall be carried out as necessary to ensure that yields are within acceptable limits.
|Avoiding mix-ups: Operations on different products shall not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.
|Labeling: At all times during processing, all materials, bulk containers, major items of equipment, and where appropriate the rooms used shall be labeled or otherwise identified with an indication of the product or material being processed and its strengths, where applicable, and the batch number, and where applicable this indication shall also mention the stage of production.
|Un-authorized entry prohibited: Access to the production premises shall be restricted to authorized personnel.
|In-process controls: In process controls are mostly performed within the production and they shall not carry any risk for the quality of the product.
|Prevention of cross-contamination and bacterial contamination in production.
|Precautions against dust: When dry materials and products are used in production, special precautions shall be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitizing materials.
|Measures against contamination: Contamination of a starting material or of a product by another material or product shall also be avoided and similarly, cross-examination shall be avoided by appropriate technical or organizational measures, as may be necessary by production segregated areas, namely;
|(a) conducting production in segregated areas.
|(b) providing appropriate airlock, pressure differentials and dust extraction.
|(c) minimizing the risk of contamination caused by re-circulation or re- entry of untreated or insufficiently treated air.
|(d) wearing and keeping protective clothing in areas where products with special risk of cross-contamination re-processed.
|(e) using, cleaning and decontamination procedures of known effectiveness, as in-effective cleaning of equipment is a common source of cross-contamination.
|(f) encourage using a ‘closed system” of production.
|(g) testing for residues where necessary;
|(h) using cleanliness status labels on equipment, showing the name of the previous product.
|Cross-contamination checks: Measures to prevent cross-contamination and their effectiveness shall be checked periodically according to the standard operation procedures.
|Microbiological monitoring: Production areas where susceptible products are processed shall undergo periodic microbiological monitoring and the bio-burden shall be kept within the specified limits.
|Processing Operations, Intermediate and Bulk Products:
|Pre-processing cleanliness checks: 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.
|In-process controls: Necessary in-process controls and environmental controls shall be carried out and recorded.
|Defective equipment: Means shall be instituted for indicating failures of equipment or of services, such as water or gas, to equipment. Defective equipment shall be withdrawn from use until the defect has been rectified.
|Cleaning containers: Containers for filling shall be cleaned before filing and attention shall be given to avoiding and removing any contaminants such as glass fragments and metal particles. Production equipment shall be cleaned according to detailed written procedures and stored only under clean and dry conditions.
|Yield deviations: Any significant deviation from expected yield shall be recorded and investigated.
|Product pipelines: Checks shall be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one are to another are connected in a correct manner.
|Water pipes: Pipes used for conveying distilled or deionized water and, where appropriate, other water-pipes shall be sanitized according to written procedures that detail the action and limits for microbiological contamination and the measures to be taken.
|Equipment calibration: Measuring, weighing, recording 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 and the date of calibration and the date when re-calibration is due shall be clearly indicated.
|Repair and maintenance: Repair and maintenance operations shall present any hazard to the quality of the products.
|Avoiding mix-ups: When the program for packaging operations is being set up particular attention shall be given to minimizing the risk of cross-contamination, mix-up, or substitutions, and different products shall not be packaged in close proximity unless there is physical segregation or the use of electronic surveillance.
|Pre-packaging checks: 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 previously used and not required for the current operation, and the line clearance shall be performed according to an appropriate checklist and recorded.
|Labeling of packaging line: The name and batch number of the product being handled shall be displayed at each packaging station or line.
|Process continuity: Normally, filling and sealing shall be followed as quickly as possible by labeling and if labeling is delayed, appropriate procedures shall be applied to ensure that no mix-up or mislabeling can occur.
|Printing operation checks: The correct performance of any printing, mode numbers or expiry dates, done separately or in the course of the packaging shall be checked and recorded, and attention shall be paid to printing by hand which shall be re-checked at regular intervals.
|Label verification: Special care shall be taken when cut labels are used and when over-printing is carried out off-line and in hand-packaging operations, roll-feed labels are normally preferable to cut labels in helping to avoid mix-up. On-line verification of all labels by automated electronic means can be helpful in preventing mix-up, but checks shall be made to ensure that electronic code readers, label counters, or similar devices are operating correctly.
|Fast color printing on labels: Printed and embossed information on packaging materials shall be distinct and resistant to fading or erasing.
|One-line packaging checks: On-line control of the product during packaging shall include at least check on;(a) the general appearance of the packages(b) whether the packages are complete(c) whether the correct products and packaging materials are used(d) whether any over-printing is correct(e) the correct functioning of line monitors(f) samples taken from the packaging line shall not be returned unless inspection is done in close the packaging proximity of line.
|Product re-introduction on packaging line: Products that have been involved in an un-usual event during packaging shall be re-introduced into the process only after special inspection, investigation, and approval by authorized personnel and a detailed record shall be kept of this operation.
|Discrepancies to be investigated: Any significant or un-usual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced shall be investigated and satisfactorily accounted for before release.
|Destruction of un-used packaging materials: Upon completion of a packaging operation, un-used batch-coded packaging materials shall be destroyed and the destruction recorded, and a documented procedure shall be followed if encoded printed materials are returned to stock.
|Section 7: Sanitation and Hygiene
|General: A high level of sanitation and hygiene shall be practiced in every aspect of the manufacture of drug products, the scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, product for cleaning and disinfection, and anything that could become a source of contamination to the product, and potential sources of contamination shall be eliminated through an integrated comprehensive program of sanitation and hygiene.
|Section 8: Validation
|General: Validation studies shall be conducted in accordance with pre-defined protocols. A written report summarizing recorded results and conclusions shall be prepared and stored. Processes and procedures shall be established on the basis of a validation study and undergo periodic re-validation to ensure that they remain capable of achieving the intended results, and particular attention shall be accorded to the validation of processing, testing and cleaning procedures.
|Process Validation to be performed as per written procedures:
|Validation of critical processes: Critical processes shall be validated, prospectively or retrospectively.
|Validation of new master formula: When any new master formula or method of preparation is adopted, steps shall be taken to demonstrate its stability for routine processing, and, the defined process, using the materials and equipment specified, shall be shown to yield a product consistently of the required quality.
|Validation of equipment and materials: Significant amendments to the manufacturing process, including any change in equipment or materials that may affect product quality and or the re-productibility of the process shall be validated.
|Section 9: Documents
|Maintenance of documents: Documents, as required under these rules, shall be meticulously maintained and regularly reviewed and kept up to date, and when a document has been revised, a system shall exist to prevent inadvertent use of the superseded version.
|Records of action: 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. The batch record shall be retained for at least one year after the expiry date of the finished product.
|Documentation systems: Data may be recorded by electronic data processing systems or by photographic or other reliable means. Master formulate and detailed standard operating procedures relating to the system in use shall be available and the accuracy of the records shall be checked and if documentation is handled by electronic data-processing method, only authorized persons shall be able to enter or modify data in the computer, and there shall be a record of changes, and deletions, access shall be restricted by passwords or their means and the entry of critical data shall be independently checked and data shall also be readily available.
|Status identification: Labels applied to containers, equipment, or premises shall be unambiguous and in the company’s agreed format. The labels of different colors may also be used in addition to the working to indicate the status such as “quarantined,” “accepted,” “rejected,” or “clear.”
|Product labeling: All finished products shall be labeled in accordance with the Drugs (Labeling and Packing) Rules 1986.
|Reference standards identification: For reference standards, the label or accompanying documents shall indicate concentration, date of manufacture, expiry, date, and storage conditions, where appropriate.
|Specification approvals: Each specification shall be approved and maintained by the quality control unit.
|Revision of specification: Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia or other official compendia or the Drugs (Specifications) Rules 1978.
|Packaging material specification: Packaging material shall conform to specifications, with emphasis placed on the compatibility of the material with the drug product it contains.
|Starting material re-assay: Documents describing testing procedures shall state the required frequency for re-assaying each starting material, as determined by its stability.
|Specifications for Intermediate and Bulk Products:
|Specifications for intermediate and bulk products shall be available if these are purchased or dispatched, of if data obtained from intermediate products are used in the evaluation of the finished product, and the specifications shall be similar to specifications for starting materials or for finished products.
|Batch Processing Records:
|General: A batch processing record shall be kept for each batch processed based on the relevant parts of the currently approved master formula and the method of preparation of such records shall be designed to avoid transcription errors.
|Checking work station: 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 and this check shall be recorded.
|Recording process operation: During processing, the following information shall be recorded at the time each action is taken, and after completion 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(c) date and times of commencement of significant intermediate stages and of completion of production(d) the name of person responsible for each stage of production(e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing)(f) the batch number and or analytical control number 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 in-process controls performed, the initials of the person(s) carrying them out, and the results obtained(i) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanation for significant deviations from the expected yield(j) note on special problems including details, with signed authorization for any deviation from the master formula
|Batch Packaging Records:
|General: A batch packaging record shall be kept for each batch or part batch processed based on the relevant parts of the packaging instructions, and the method of preparing such records shall be designed to avoid transcription errors.
|Pre-packing line checks: Before any packaging operation beings, 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. There checks shall be recorded.
|Recording of packaging operation: 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 obtained, the quantity actually obtained, and the reconciliation(b) the date(s) and time(s) of the packaging operations(c) the name of the responsible person carrying out the packaging operation(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 reference to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product un-packed or a record or 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 batch number, expiry date, and any additional overprinting(h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person(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 and adequate reconciliation
|Recording batch numbers: Batch-number allocation shall be immediately recorded in a logbook, and the record shall include date of allocation, product identity, and size of batch.
|Analytical records: Analysis records shall include at least the following namely;(a) the name of the material or product and, where applicable, dosage form(b) the batch number and, where appropriate, the manufacturer and/or supplier(c) references to the relevant specifications and testing procedures(d) test results, including observations and calculations, and reference to any specifications (limits)(e) dates of testing(f) the initials of the persons who performed the testing(g) the initials of the persons who verified the testing and the calculations, where appropriate(h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.
|Finished product release procedure: 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.
|Recording batch distribution: Records shall be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary.
|Standard operating procedures: Standard operating procedures and associated records of actions taken or, where appropriate, conclusions reached shall be available at the premises for;(a) equipment assembly and validation(b) analytical apparatus and calibration(c) maintenance, cleaning, and sanitization(d) personnel matters including qualification, training, clothing, and hygiene(e) environmental monitoring & pest control(g) complaints & recalls(h) status
|Equipment logbooks: Logbooks shall be kept with major and critical equipment as identified by the licensee and shall record, as appropriate, any validations, calibrations, maintenance, cleaning, or repair operations including dates and the identity of the people who carried out these operations.
|Equipment utilization record: The use of major and critical equipment and the areas where products have been processed shall be appropriately recorded in chronological order.
cGMP Internal Audit Schedule
cGMP Internal Auditors List