Review Article Good practices in quality control in pharmaceutical industry - Overview of regulatory guidelines Chagi Venkatesh*, S. B. Puranik ABSTRACT Good practices in quality control (QC) department need to monitor the analytical process at least daily for normal and abnormal controls in tests. Along with the submitted sample, there should be a state of reason why the analysis has been requested for testing. How to maintain records of each performed tests along with raw data for quick reference. Good practices in QC, controlling of starting, bulk and finished product materials, batch record view and requirements of testing of starting, packing materials, and stability tests were some of the topics discussed in this article. The main aim of this article was to give an overview of good practices in the QC department in pharmaceutical industry as per the different regulatory guidelines, namely, World Health Organization, Schedule M, United State Food and Drug Administration, Medicines and Healthcare Regulatory Authority, Therapeutic Goods Administration, and Pharmaceutical Inspection Cooperation Scheme. Good practices help in the production of accurate results with the knowledge of sample preparation techniques. KEY WORDS: Good practices, Medicines and healthcare regulatory authority, Schedule M, Therapeutic goods administration/ pharmaceutical inspection cooperation scheme, United States food and drug administration World health organization INTRODUCTION Quality control (QC) laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents, and records. The design of the laboratories should take into account the suitability of construction materials, prevention of fumes and ventilation. There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological, and radioisotope laboratories. A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors, or where it is necessary to isolate the instruments as inferred by the World Health Organization (WHO) in 12.33 12.36. Access this article online Website: jprsolutions.info ISSN: 0974-6943 Schedule M describes this requirement in section 5.2 and 5.3 apart from that it has indicated a separated requirement for sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents, and records. QC is concerned with sampling, specifications, and testing as well as the organization, documentation and release procedures which ensure that the necessary and relevant tests are carried out and those materials are neither released for use nor products released for sale or supply until their quality has been judged satisfactory. QC is not only confined to laboratory operations but also must be involved in all decisions which may concern the quality of the product. The independence of QC from production is considered fundamental to the satisfactory operation of QC. DISCUSSION Regulatory Guidelines for QC in Pharmaceutical Industry as per the WHO WHO describes the QC in Pharmaceutical industries. QC areas QC laboratories should be separated from production areas. Areas where biological, microbiological, or Department of Quality Assurance, PRIST University, Thanjavur, Tamil Nadu, India *Corresponding author: Chagi Venkatesh, PRIST University, Thanjavur, Tamil Nadu, India. Phone: +91-9845145925, E-mail: venkatesh.chagim@gmail.com Received on: 02-01-2017; Revised on: 27-01-2018; Accepted on: 20-02-2018 Journal of Pharmacy Research Vol 12 Issue 4 2018 489
radioisotope test methods are employed should be separated from each other. QC laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and-cross contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents, and records. The design of the laboratories should take into account the suitability of construction materials, prevention of fumes, and ventilation. There should be separate air supply to laboratories and production areas. Separate air handling units and other provisions are needed for biological, microbiological, and radioisotope laboratories. Good practices in QC QC is part of good manufacturing practice (GMP) 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 neither released for use nor products released for sale or supply, until their quality has been judged to be satisfactory. QC is not confined to laboratory operations but may be involved in many decisions concerning the quality of the product. The independence of QC from production is considered fundamental. Each manufacturer should have a QC function. The QC function should be independent of other departments and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his or her disposal. Adequate resources should 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 should be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; b. Samples of starting materials, packaging materials, intermediate products, bulk products and finished products should be taken by methods, and personnel approved of by the QC department; c. Qualification and validation; d. Records should be made (manually and/or by recording instruments) 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 should contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorization; the ingredients should be of the required purity, in their proper container and correctly labeled; f. Records should be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications; product assessment should 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 should be retained to permit future examination of the product if necessary; the retained product should be kept in its final pack unless the pack is exceptionally large. QC as a whole will also have other duties, such as to establish, validate and implement all QC procedures, to evaluate, maintain, and store the reference standards for substances, to ensure the correct labeling of containers of materials and products, to ensure that the stability of the active pharmaceutical ingredients and products is monitored, to participate in the investigation of complaints related to the quality of the product, and to participate in environmental monitoring. Control of starting materials and intermediate, bulk, and finished products All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected. Samples should be representative of the batches of material from which they are taken by the approved written procedure. Sampling should be carried out to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling. Care should be taken during sampling to guard against contamination or mix-up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Some particularly hazardous or potent materials may require special precautions. Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment. Each sample container should bear a label indicating: a. The name of the sampled material; b. The batch or lot number; c. The number of the container from which the sample has been taken; d. The number of the sample; e. The signature of the person who has taken the sample; f. The date of sampling. 490 Journal of Pharmacy Research Vol 12 Issue 4 2018
Out-of-specification results obtained during testing of materials or products should be investigated by an approved procedure. Records should be maintained. Test requirements for starting and packaging materials Before releasing a starting or packaging material for use, the QC manager should ensure that the materials have been tested for conformity with specifications for identity, strength, and purity and other quality parameters. An identity test should 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 labeled. Each batch (lot) of printed packaging materials should be examined following receipt. In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes there liability 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 should be originals (not photocopies), or otherwise have their authenticity assured. Certificates should contain at least the following information: a. Identification (name and address) of the issuing supplier; b. Signature of the competent official, and statement of his or her qualifications; c. The name of the material tested; d. The batch number of the material tested; e. The specifications and methods used; f. The test results obtained; g. The date of testing. In-process control In-process control records should be maintained and form a part of the batch records of finished products. For each batch of medicines product, there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification before release. Products failing to meet the established specifications or any other relevant quality criteria should be rejected. Batch record review QC records should 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 its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action. Retention samples from each batch of the finished product should be kept for at least 1-year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. Samples of active starting materials should be retained for at least 1-year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases, and water) should be retained for a minimum of 2 years if their stability allows. Retention samples of materials and products should be of a size sufficient to permit at least two full reexaminations. [1] Regulatory Guidelines for QC in Pharmaceutical Industry as per Schedule M Separate areas shall be provided each for physicochemical, biological, microbiological or radioisotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis. QC Laboratories shall be designed appropriately for the operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and crosscontamination. Sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents, and records. Separate air handling units and other requirements shall be provided for biological, microbiological, and radioisotopes testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purposes. QC laboratory shall be divided into separate sections i.e., for chemical, microbiological, and wherever required, biological testing. These shall have adequate area for basic installation and for ancillary purposes. The microbiology section shall have arrangements such as airlocks and laminar airflow workstation, wherever considered necessary. [2] Regulatory Guidelines for QC in Pharmaceutical Industry as per United State Food and Drug Administration General requirements The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the QC unit. Journal of Pharmacy Research Vol 12 Issue 4 2018 491
Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Testing and release for distribution For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, before release. Where sterility and/ or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released before the completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible. There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms. Acceptance criteria for the sampling and testing conducted by the QC unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical QC criteria as a condition for their approval and release. The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished. Drug products failing to meet established standards or specifications and any other relevant QC criteria shall be rejected. Reprocessing may be performed. Stability testing There shall be a written testing program designed to assess the stability characteristics of drug products. The written program shall be followed and shall include: a. Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability; Storage conditions for samples retained for testing; b. Reliable, meaningful, and specific test methods; c. Testing of the drug product in the same containerclosure system as that in which the drug product is marketed; d. Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted. An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Allergenic extracts that are labeled No U.S. Standard of potency are exempt from the requirements of this section. Special testing requirements For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed. For each batch of ophthalmic ointment, there shall be appropriate testing to determine conformance to specifications regarding the presence of foreign particles and harsh or abrasive substances. The test procedures shall be in writing and shall be followed. Laboratory animals Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained and controlled in a manner that assures their suitability for their intended use. They shall be identified, and adequate records shall be maintained showing the history of their use. [3] Regulatory Guidelines for QC in Pharmaceutical Industry as per MHRA General Each holder of a manufacturing authorization should have a QC department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources should be available to ensure that all the QC arrangements are effectively and reliably carried out. The QC department as a whole will also have other duties, such as to establish, validate and implement all QC procedures, keep the reference samples of materials and products, ensure the correct labeling of containers of materials and products, ensure the monitoring of the stability of the products, and participate in the investigation of complaints related to the quality of the product. All these operations should be carried out by written procedures and, where necessary, recorded. Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with finished product specification, and examination of the final finished pack. QC personnel should have access to production areas for sampling and investigation as appropriate. Good QC laboratory practice Control laboratory premises and equipment should meet the general and specific requirements for QC 492 Journal of Pharmacy Research Vol 12 Issue 4 2018
areas. The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles, contract analysis, can be accepted for particular reasons, but this should be stated in the QC records. Documentation Laboratory documentation should follow the principles. An important part of this documentation deals with QC and the following details should be readily available to the QC Department: Specifications; Sampling procedures; Testing procedures and records (including analytical worksheets and/or laboratory notebooks); Analytical reports and/or certificates; Data from environmental monitoring, where required; Validation records of test methods, where applicable; and procedures for and records of the calibration of instruments and maintenance of equipment. For some kinds of data (e.g., analytical tests results, yields, and environmental controls) it is recommended that records are kept in a manner permitting trend evaluation. In addition to the information which is part of the batch record, other original data such as laboratory notebooks and/or records should be retained and readily available. Sampling The sample taking should be done in accordance with approved written procedures that describe: The method of sampling; The equipment to be used; The amount of the sample to be taken; Instructions for any required subdivision of the sample; The type and condition of the sample container to be used; The identification of containers sampled; Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials; The storage conditions; Instructions for the cleaning and storage of sampling equipment. Reference samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g., beginning or end of a process). Sample containers should bear a label indicating the contents, with the batch number, the date of sampling, and the containers from which samples have been drawn. Testing Analytical methods should be validated. All testing operations described in the marketing authorization should be carried out according to the approved methods. The results obtained should be recorded and checked to make sure that they are consistent with each other. Any calculations should be critically examined. The tests performed should be recorded, and the records should include at least the following data: a. Name of the material or product and, where applicable, dosage form; b. 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 e. any certificates of analysis; f. Dates of testing; g. Initials of the persons who performed the testing; h. Initials of the persons who verified the testing and the calculations; i. Where appropriate; j. A clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person. All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by QC and the results recorded. Special attention should be given to the quality of laboratory reagents, volumetric glassware and solutions, reference standards and culture media. They should be prepared in accordance with written procedures. Laboratory reagents intended for prolonged use should be marked with the preparation date and the signature of the person who prepared them. The expiry date of unstable reagents and culture media should be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardization and the last current factor should be indicated. Where necessary, the date of receipt of any substance used for testing operations (e.g., reagents and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases, it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use. Animals used for testing components, materials or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use. Journal of Pharmacy Research Vol 12 Issue 4 2018 493
On-going stability program After marketing, the stability of the medicinal product should be monitored according to the continuous appropriate program that will permit the detection of any stability issue (e.g., changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package. The purpose of the on-going stability program is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labeled storage conditions. This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the program of bulk product. For example, when the bulk product is stored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability of the packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediates that are stored and used over prolonged periods. Stability studies on the reconstituted product are performed during product development and need not be monitored on an on-going basis. However, when relevant, the stability of reconstituted product can also be monitored. The on-going stability program should be described in a written protocol following the general rules of Chapter 4 and results formalized as a report. The equipment used for the on-going stability program (stability chambers among others) should be qualified and maintained following the general rules of Chapter 3 and Annex 15. The protocol for an on-going stability program should extend to the end of the shelf life period and should include, but not be limited to, the following parameters: Number of batch(es) per strength and different batch sizes, if applicable; Relevant physical, chemical, microbiological, and biological test methods; Acceptance criteria; Reference to test methods; Description of the container closure system(s); Testing intervals (time points); Description of the conditions of storage (standardized ICH conditions for Long-term testing, consistent with the product labeling, should be used); Other applicable parameters specific to the medicinal product. The protocol for the on-going stability program can be different from that of the initial long-term stability study as submitted in the marketing authorization dossier provided that this is justified and documented in the protocol. The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program (unless none are produced during that year). For products where ongoing stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk-benefit approach. The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol. In certain situations, additional batches should be included in the on-going stability program. For example, an on-going stability study should be conducted after any significant change or significant deviation to the process or package. Any reworking, reprocessing, or recovery operation should also be considered for inclusion. Results of on-going stability studies should be made available to key personnel and, in particular, to the qualified person(s). Where on-going stability studies are carried out at a site other than the site of manufacture of the bulk or finished product, there should be a written agreement between the parties concerned. Results of on-going stability studies should be available at the site of manufacture for review by the competent authority. Out-of-specification or significant atypical trends should be investigated. Any confirmed out-ofspecification result or significant negative trend should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with Chapter 8 of the GMP Guide and in consultation with the relevant competent authorities. A summary of all the data generated, including any interim conclusions on the program, should be written and maintained. This summary should be subjected to periodic review. [4] Regulatory Guidelines for QC in Pharmaceutical Industry as per Therapeutic Goods Administration/ Pharmaceutical Inspection Cooperation Scheme General Each holder of a manufacturing authorization should have a QC department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources should 494 Journal of Pharmacy Research Vol 12 Issue 4 2018
be available to ensure that all the QC arrangements are effectively and reliably carried out. The principal duties of the head of QC. The QC department as a whole will also have other duties, such as to establish, validate and implement all QC procedures, keep the reference samples of materials and products, ensure the correct labeling of containers of materials and products, ensure the monitoring of the stability of the products, and participate in the investigation of complaints related to the quality of the product. All these operations should be carried out in accordance with written procedures and, where necessary, recorded. Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with finished product specification, and examination of the final finished pack. QC personnel should have access to production areas for sampling and investigation as appropriate. Good QC laboratory practice Control laboratory premises and equipment should meet the general and specific requirements for QC areas. The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles, Contract Analysis, can be accepted for particular reasons, but this should be stated in the QC records. Documentation Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with QC and the following details should be readily available to the QC department: Specifications; Sampling procedures; Testing procedures and records (including analytical worksheets and/or laboratory notebooks); Analytical reports and/or certificates; Data from environmental monitoring, where required; Validation records of test methods, where applicable; Procedures for and records of the calibration of instruments and maintenance of equipment. Any QC documentation relating to a batch record should be retained for 1-year after the expiry date of the batch. For some kinds of data (e.g., analytical tests results, yields, and environmental controls) it is recommended that records in a manner permitting trend evaluation be kept. In addition to the information which is part of the batch record, other original data such as laboratory notebooks and/or records should be retained and readily available. Sampling The sample taking should be done in accordance with approved written procedures that describe: The method of sampling; The equipment to be used; The amount of the sample to be taken; Instructions for any required subdivision of the sample; The type and condition of the sample container to be used; The identification of containers sampled; Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials; The storage conditions; Instructions for the cleaning and storage of sampling equipment. Reference samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process. Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn. Reference samples from each batch of finished products should be retained until 1-year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. Samples of starting materials (other than solvents, gases, and water) should be retained for at least 2 years after the release of the product if their stability allows. This period may be shortened, if their stability, as mentioned in the relevant specification, is shorter. Reference samples of materials and products should be of a size sufficient to permit at least a full reexamination. Testing Analytical methods should be validated. All testing operations described in the marketing authorization should be carried out according to the approved methods. The results obtained should be recorded and checked to make sure that they are consistent with each other. Any calculations should be critically examined. The tests performed should be recorded and the records should include at least the following data: a. Name of the material or product and, where applicable, dosage form; b. Batch number and, where appropriate, the manufacturer and/or supplier; c. References to the relevant specifications and testing procedures; Journal of Pharmacy Research Vol 12 Issue 4 2018 495
d. Test results, including observations and calculations, and reference to any certificates of analysis; e. Dates of testing; f. Initials of the persons who performed the testing; g. 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. All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by QC and the results recorded. Special attention should be given to the quality of laboratory reagents, volumetric glassware and solutions, reference standards, and culture media. They should be prepared in accordance with written procedures. Laboratory reagents intended for prolonged use should be marked with the preparation date and the signature of the person who prepared them. The expiry date of unstable reagents and culture media should be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardization and the last current factor should be indicated. Where necessary, the date of receipt of any substance used for testing operations (e.g., reagents and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases, it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use. Animals used for testing components, materials or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use. [5] SUMMARY OF REGULATIONS Development of Theory for QC in Pharmaceutical Based on the above comparative analysis and discussion on the QC department in pharmaceutical as per the different regulatory guidelines below is the theory developed which is common for the entire regulatory requirement. Following of the below common theory shall suffice the requirements of all the regulatory guidelines with respect to the QC department. Construction of QC Department QC laboratories shall be independent of the production areas. Separate areas shall be provided each for physicochemical, biological, microbiological, or radioisotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis. QC laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and crosscontamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents reagents, and records. The design of the laboratory should take into account the suitability of construction materials, prevention of fumes, and ventilation. There should be separate air supply to laboratories and production areas. Separate air handling units and other provisions needed for biological, microbiological, and radioisotope laboratories. A separate room needed for instruments to protect them against electrical interference, vibration contact with excessive moisture, and other external factors. A separate room needed for wet analysis to protect them against electrical interference. A separate room needed for storage of control samples such as raw material and packaging material. Principle QC is concerned with sampling, specifications and testing as well as the organization, documentation, and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. QC is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of QC from production is considered fundamental to the satisfactory operation of QC. General requirements of QC a. The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the QC unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified. b. Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, 496 Journal of Pharmacy Research Vol 12 Issue 4 2018
standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include 1. Determination of conformity to applicable written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration. 2. Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified. 3. Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified. 4. The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event. Accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used. Testing and Release for Distribution a. For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, before release. Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released before the completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible. b. There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms. c. Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed. d. Acceptance criteria for the sampling and testing conducted by the QC unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical QC criteria as a condition for their approval and release. The statistical QC criteria shall include appropriate acceptance levels and/or appropriate rejection levels. e. The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. f. Drug products failing to meet established standards or specifications and any other relevant QC criteria shall be rejected. Reprocessing may be performed. Before acceptance and use, reprocessed material should meet appropriate standards, specifications, and any other relevant criteria. Contract Testing Laboratories The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories analysis can be accepted based on evaluation of laboratory control department. Different Testing Requirements for Various Products a. Sterile product required such as sterility or pyrogenfree. b. Ophthalmic ointment to determine the presence of foreign particles or abrasive substance. c. Controlled release dosage to study the rate of release for each active ingredient. Reserve Samples Reserve samples shall be stored for each batch and ingredients at least twice the quantity of samples and shall be retained for 1-year after the expiration date of the last lot of the drug product contains the active ingredient. In case of radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for 3months after the expiration date of the last lot of drug product. For OTC drug products is an exempt for bearing an expiration date, those sample shall be retained for 3 years after distribution of the last lot of drug product. Reserve samples shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample. Documentation An important part of this documentation deals with QC and the following details should be readily available to the QC department: Journal of Pharmacy Research Vol 12 Issue 4 2018 497
Specifications; Sampling procedures; Testing procedures and records (including analytical worksheets and/or laboratory notebooks); Analytical reports and/or certificates; Data from environmental monitoring, where required; Validation records of test methods, where applicable; Procedures for and records of the calibration of instruments and maintenance of equipment. Any QC documentation relating to a batch record should be retained for 1-year after the expiry date of the batch and at least 5 years after the certification. For some kinds of data (e.g. analytical tests results, yields, and environmental controls) it is recommended that records are kept in a manner permitting trend evaluation. In addition to the information which is part of the batch record, other original data such as laboratory notebooks and/or records should be retained and readily available. On-going Stability Program The protocol for an on-going stability program should extend to the end of the shelf life period and should include, but not be limited to, the following parameters: Number of batch (es) per strength and different batch sizes, if applicable; Relevant physical, chemical, microbiological, and biological test methods; acceptance criteria; Reference to test methods; Description of the container closure system(s); Testing intervals (time points); Description of the conditions of storage (standardized ICH conditions for long-term testing, consistent with the product labeling, should be used); Other applicable parameters specific to the medicinal product. The protocol for the on-going stability program can be different from that of the initial long-term stability study as submitted in the marketing authorization dossier provided. The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program (unless none are produced during that year). For products where on-going stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk-benefit approach. The principle of bracketing and matrixing designs may be applied, if scientifically, justified in the protocol. In certain situations, additional batches should be included in the on-going stability program. For example, an on-going stability study should be conducted after any significant change or significant deviation to the process or package. Any reworking, reprocessing or recovery operation should also be considered for inclusion. Results of on-going stability studies should be made available to key personnel and, in particular, to the qualified person(s). Where on-going stability studies are carried out at a site other than the site of manufacture of the bulk or finished product, there should be a written agreement between the parties concerned. Results of on-going stability studies should be available at the site of manufacture for review by the competent authority. CONCLUSION Out-of-specification or significant atypical trends should be investigated. Any confirmed out-ofspecification result, or significant negative trend, should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered and consult with the relevant competent authorities. A summary of all the data generated, including any interim conclusions on the program, should be written and maintained. This summary should be subjected to periodic review. REFERENCES 1. WHO -Annex 3 -Good Manufacturing Practices for Pharmaceutical Products-Building and Facilities Section 12 to 16. WHO Technical Report Series, No.961; 2011. Available from: http:// www.who.int/medicines/areas/quality_safety/quality_assurance/ GMPPharmaceuticalProductsMainPrinciplesTRS961Annex3. pdf. 2. Schedule M- Part I -Good Manufacturing Practices for Premises and Materials-In General Requirements of Premises and Materials for Pharmaceutical Products. Available from: http://www.cdsco.nic.in/writereaddata/schedulem(gmp)6. pdf. 3. USFDA-CFR-Part 211-Current Good Manufacturing Practice for Finished Pharmaceuticals-Subpart C-Buildings and Facilities. Available from: https://www.law.cornell.edu/cfr/text/21/part-211. 4. Guidance on Good Manufacturing Practice (GMP) -EU Guidance on Good Manufacturing Practice PART I: Basic Requirements for Medicinal Products-chapter-3 Premises and equipment. Available from: https://ec.europa.eu/health/sites/ health/files/files/eudralex/vol4/2017_11_22_guidelines_gmp_ for_atmps.pdf. 5. TGA/PICS - guide to Good Manufacturing Practice for Medicinal Products Part I Ch. 3 premises and equipment. Available from: https://www.tga.gov.au/sites/default/files/ manuf-pics-gmp-medicines-part1.pdf. 498 Journal of Pharmacy Research Vol 12 Issue 4 2018