Auditing for Sterile Production Area

Audits and Regulatory Compliance

1. AUDITS AND RREGULATORY COMPLIANCE (MQA-203T) UNIT IV Auditing of Microbiological Laboratory Presented By V. Manikandan, Roll No. 2061050002, M. Pharm (Pharmaceutical Quality Assurance) – I Year, Department of Pharmacy, Annamalai University. Submitted to Dr. K. Devi, M. Pharm., Ph. D, Assistant Professor, Department of Pharmacy, Annamalai University.

2. Definition of Audit Quality audit is defined as a systematic and independent examination to determine whether activities and related results comply with planned arrangements and whether these arrangements are implemented effectively and are suitable to achieve objectives. Scope and Objectives To ensure quality of the Product To assess effectiveness of QA system It permits timely correction of problems It established high degree of confidence

3. Audit schedule The most critical and failure-prone activities should be covered most frequently. Schedule can be structured to fit in around peak workload times throughout a year. Audit schedule can be simply documented as a matrix plan with audits set by month. The auditing process, Contact auditee Prepare checklists and plan Briefing Actual audit – information gathering Preparation of report

4. Action on findings Follow up audit if required Remember Audits are of the system as a whole and not the person. Prepare thoroughly for the audit Use checklists Checklist that is generic and covers standard issues. Checklist that is tailored around the procedure to be audited. Checklist that is as a result of a document review.

5. Gather sufficient evidence to substantiate the findings in the report. Record the particular examples that were reviewed. Have a look at work in action if possible – this can establish if there are inconsistencies between actual procedure and work in practice. Types of questions to use What would you do if….? I’m not quite sure what you mean by that. Could you perhaps explain it another way? Is this always done this way? Listen actively. Be reassuring when necessary. Bring the auditee back on track when necessary.

6. Always be clear of what you are hearing – if necessary ask for clarification. Report writing Remember to give praise where praise is due. Make the findings constructive and definitive. The findings must be based upon actual fact and evidence sighted during the audit. Follow up on audits Corrective actions – designed to fix up the non conformance that has already occurred Remember to get to the root cause of why the non conformance actually occurred. Preventive actions – to prevent non conformances occurring by taking appropriate action where there could be potential for an issue to arise. Set realistic timeframes for addressing the findings.

7. Example of an Audit Schedule Month Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Activity to be audited Organization and Management x Staff/Training records x x Equipment x x Proficiency programs x x Test methods x x calibrations x x Sample receipt x

8. P rocess for A udit A process audits an examination of results to determine whether the activities, resources and behavior that cause them are being managed efficiently and effectively. A process audits not simply following a trail through a department from input to output, this is a transaction audit. How to Audit a Manufacturing Process ? An audit of a manufacturing process is a comprehensive examination of the process to verify that it is performing as intended. Processes generate results, and process audits determine if the results are accurate and being generated by an effectively managed process.

9. Manufacturing process audits should ensure that procedures are properly followed, problems are quickly corrected, there is consistency in the process, and there is continuous improvement and corrective action as needed. R easons for conducting a manufacturing audit Assures procedures reflect actual practice (what we say is what we do) Uncovers inaccuracies so they can be quickly corrected Reveals the consistency of a process (from person to person, or day to day) Demonstrates a proactive approach to process improvement Encourages ongoing corrective action

10. A good manufacturing audit requires following actions Announcement in advance. Manufacturing audits are not meant to catch people doing something wrong. On the contrary, during an audit you hope to catch people doing things right. A rating scheme to classify problems discovered. A rating scheme allows you to rank problems in order to prioritize corrective actions. Trained auditors. Auditors should be familiar with both the area they are observing and with auditing techniques. Planning and clear procedures. A manufacturing audit is more than just walking into a work area and looking for trouble.

11. The steps listed below can help in planning and conducting an audit Select a process to be audited : Prioritize the processes that can be audited in terms of importance and risk to the overall operation. Begin auditing the highest-risk areas first. Select a team to conduct the audit : The audit team should be familiar with the process being audited. They should also be familiar with audit techniques such as sampling and analyzing results. They must have the necessary expertise to identify problems and determine the corrective actions needed. Decide how often the process should be observed (the frequency of the audit): If there are significant problems or noncompliance, the process should be observed more often until the situation is under control. Announce the audit in advance so there are no surprises : The objective is to improve the process, which will require the cooperation of everyone involved

12. Set up an audit schedule for the entire shift and follow the established audit schedule : The number of observations will be your sample of the work for that shift. The audit schedule should be determined in advance and should be as random as possible. Once established, the audit schedule should be followed to provide results based on a random sample. Document any problems discovered and inform all those affected : The idea is not to assign blame but to find a solution. The problems discovered become the basis for corrective actions and follow-up. Everyone affected by the problem should be informed so they are aware and can provide input to the resolution. Also, the process being audited will likely affect other processes in the over-all operation. Determine and perform corrective actions : Let employees make suggestions for corrective actions and select any that are appropriate, but management should make the final decision as to which corrective actions to implement.

13. Monitor corrective-action results : Perform follow-up monitoring to determine if the corrective actions have actually eliminated the problem or if further action is required. Also verify that no new problems have developed or entered into the process. Product and Process Information Process Audit A process audits an examination of results to determine whether the activities, resources and behavior that cause them are being managed efficiently and effectively. A process audits not simply following a trail through a department from input to output -this is a transaction audit.

14. In contrast with rear-facing product inspections, process audits focus on how your team prepares, produces, packages and distributes those products. This approach provides a more comprehensive view of the value stream than product audits, which only sample the finished output. Process audits look at details of manufacturing process such as, Fabrication steps Safety measures Temperature settings Pressure readings Calibration of gauges

15. Product Audit The product audits the assessment of the final product/service and its qualification for use evaluated versus the intent of the purpose of the product/service. It ensures a thorough inspection of a final product before delivery to a supplier or a customer. Product audits take place after manufacturing is complete, but before the product reaches the customer. If a product doesn’t meet standard requirements or specifications, the auditor documents the findings and logs a non-conformance. While each company will have its own procedures for addressing non-conformances, the process typically includes, Identifying the problem Containing the non-conformance

16. Reworking or repairing the products, if possible Disposing of nonconforming products if you can’t rework or repair them Determining the necessary countermeasures for preventing recurrence Product audits can help a manufacturer improve quality, profits, customer satisfaction, and loyalty. An effective manufacturing process audit program that ensures the highest level of quality requires both product and process audits. Though nearly all manufacturers conduct product audits, fewer of them have defined process audit procedures in place Quality goals for product audit Standardizing processes to ensure compliance with specific requirements such as time, components, accuracy or temperature. Continuously reducing risk through systematic identification and correction of process errors.

17. Monitoring key metrics for evaluating overall process performance. Assessing effectiveness of process controls such as procedures, instructions and specifications. Reviewing production resources, work standards and the manufacturing environment itself. D ifference between Process audit & Product audit Process Audit Product Audit Auditor will concentrate on process at each stage & its relevant parameters process parameters like temperature, pressure, speed etc. Auditor will concentrate only on output of the process & its relevant parameters.

18. SOP in Microbiology Laboratory SOPs and equipment manuals should be available for all instrumentation. If equipment maintenance logbooks are used, they should be up-to-date with complete entries and controlled. SOPs for laboratory equipment should include: Maintenance frequency and maintenance activities Calibration (if appropriate) Cleaning, and operation Method of cleaning/disinfection, cleaning agents, and frequency of cleaning Operation of equipment including monitoring frequency and documentation Emergency procedures in the case of a power outage or temperature deviation

19. Qualification of Equipment Critical instruments and equipment should be qualified and calibrated and included in a routine calibration program. Equipment used to provide a controlled temperature should be set at the appropriate temperature for its intended use. Qualification should include temperature mapping where appropriate as for walk-in incubators and ovens. Autoclave load patterns should be established, assigned to cycles, and tested. Tests should include heat penetration studies and biological challenge tests. If media is sterilized in house it should take into account the heat sensitivity of some media and the risk of ‘over sterilising ’ the media. Autoclave re-qualification should occur periodically, according to established change control procedures and with associated test protocols to verify that the autoclave has remained in a validated state.

20. Stock cultures Microbial cultures are pure strains of one particular microorganism. Stock cultures are used as inoculum for testing or reference samples. The cultures can be either isolated from an environmental sample or purchased commercially as a pure strain. Microbial cultures may be kept almost indefinitely if care is taken during the transfer process. Microbial cultures should only be transferred or “passed” five successive times if they will be used as positive controls or in assays. The passages and dates of transfer should be documented. Stability and maintenance of cultures should be documented. Once an agar slant containing a culture is removed from storage, it should not be used again. Storage conditions for cultures should be monitored and documented. Cultures may be frozen onto sterile glass beads and stored at -20 C.

21. They may also be stored under nitrogen in a mixture of glycerol, to prevent cell breakage upon thawing. Cultures may also be lyophilized (freeze dried) and kept in a powder state. The laboratory should have an SOP that includes storage conditions for microbial cultures used in the laboratory. Microbial cultures and test plates with growth should be inactivated before being sent for disposal. The procedures for inactivation should be in compliance with the site’s waste disposal policy and procedure.

22. The test then compares the level of microorganisms found in a control sample versus the test sample over a period of 28 days. This testing is performed as part of a stability study. It is necessary to determine if a preservative system will continue to be effective over the product’s shelf life and if the preservative system is compatible with the formulation of the product. If a formulation changes or a significant product or packaging change occurs, it is necessary to retest the effectiveness of the preservative system. Antimicrobial Effectiveness Test The Antimicrobial Effectiveness Test, a test described in the pharmacopoeias, demonstrates the effectiveness of the preservative system in a product. A product is tested against a controlled quantity of different types of microorganisms.

23. Growth Promotion Testing This test is performed to indicate that the selected test media is capable of supporting microbial growth. Environmental isolates may be used in addition to indicator organisms to test growth promotion. Organisms should be incubated at their optimum temperature so that erratic results are not generated. Identity Testing of Microorganisms Microbial organisms found through testing may need to be identified. The degree of identification needed and when should be specified in an SOP. The site should have an approved SOP that contains the test method in use. Identification may be performed through a series of testing with selected growth media or through a rapid microbial identification system.

24. Rapid microbial systems use electronic instruments designed specifically for microbial ID. The equipment should be validated and there should be validated written procedures for operation and maintenance. Cultures of known microorganisms should be used as positive controls to verify that the test is working properly. There should be an SOP in place describing the test parameters and the operating conditions. Environmental Monitoring This testing may include personnel, surface, water, air and other specialized testing. Agar test samples from the air, personnel, and surfaces are incubated appropriately to grow both fungal and bacterial contaminants. The temperature ranges used for incubation may be based upon the relevant compendia, regulatory guidance or validated conditions.

25. If growth appears, the laboratory should isolate the particular organisms, and characterize them as appropriate. When to characterize and to what level should be described in SOP. All isolates and characterizations should be documented as to date, and type of sample. Key Parameters in Auditing a Microbiological Laboratory Prior to the audit Find out which products are tested in the laboratory Find out which methods/specifications should be used Request a list of laboratory SOPs. Request a list of laboratory equipment.

26. Request a list of laboratory deviations, out of specifications and/or out of trend investigations from the previous 12 months. Review previous audits to determine if there are pending actions. During the audit Conduct a walkthrough of the laboratory. Verify that there are designated areas for performing various testing functions. Verify that the laboratory is maintained in a clean and orderly fashion. Verify that the laboratory is in good repair, (i.e. no chipped paint on walls, no loose ceiling tiles, etc.). Verify that there is physical and dress discipline segregation from other laboratories.

27. Verify that personnel are following the dress code for the area. Verify that all reagents and chemicals are labeled with expiration date and have not expired. Verify that equipment has been calibrated. Verify that incubators, freezers and refrigerators are temperature monitored. Verify that incubators have been subject to temperature mapping studies. Ensure that documentation is in place and approved. Verify that the laboratory has approved SOPs on the following general topics, Cleaning of laboratory and equipment. Maintenance and disposal of laboratory cultures.

28. Operation, maintenance, and cleaning of incubators, ovens, refrigerators/cold vaults, hoods, and water baths. Transfer methods, maintenance and storage of stock cultures. Operation, maintenance, and cleaning of autoclaves. Managing a microbiological laboratory out of specification result. Managing a laboratory spill. Preparation and storage of stock solutions, reagents and culture media. Verify that the laboratory has a system for collecting and maintaining data. If the system is computer based, it must be validated and comply with applicable ERES requirements. Review data and verify that the chosen product is tested as required.

29. Ensure that the test method has been qualified for the product. Ensure that a procedure is followed for sampling and handling samples. Verify that samples are labeled properly and uniquely identified. Verify that there is a system in place that assures samples are stored under correct conditions. Verify that the sample is signed in using a well documented and established procedure. Verify that there is a documented procedure for logging samples out of the lab.

30. General areas interest in the building Walls and celling's Floors and drains Doors ,windows and fittings Equipment P ipelines Walls and celling's Moulds are most commonly encountered microbes on walls celling’s , particularly when poor ventilation, temperature, and relative humidity control lead to high level of moisture. C ontamination may be excessive where damaged surfaces expose the underlying plaster.

31. S urfaces should be smooth ,impervious and cleanable; damaged surfaces should be repaired promptly. Floors and drains Flours should be impervious to water, cleanable and resilient to day to day wear and tear. F lours should be laid flat to minimize the risk of excessive surface water(e.g. washing bays) or ideally should slope towards drain. The auditor should pay particular attention to joints, seals and floor to wall coving to ensure that surfaces should be repaired promptly. Where floor drainage channels are needed , they should be open shallow easy to clean drain effectively.

32. The auditor must be aware that any ‘static’ water can act as reservoirs for gram negative organisms , particularly pseudomonas species. Doors, windows and fittings These should be flush-fitting whenever possible. Wood readily absorbs moisture and can generate high number of moulds; where present, it should be sealed with a high –glass paint and any surface damage repaired immediately. Equipment The ability of bacteria to attach to surfaces such as stainless steel and plastic and survive should not be under estimate. Every piece of equipment has its own particular nooks and crannies where microbiological contamination can reside; internal threads and dead legs cause particular problem.

33. Cleaning of equipment Cleaned equipment can be readily decontaminated before use. The auditor should review the quality water used in final rinsing stage and how equipment is dried and stored to minimize the risk of contamination by pseudomonas and other gram-negative bacteria . Pipelines Pipeline must be completely drainable to ensure that trapped fluid does not provide a hospitable environment for growth of bacteria. Internal surfaces should be smooth and polished to minimize pits where microbes may lodge. Joints and welds should be kept a minimum, since they may provide a protective haven for a microorganism. Its sealed with lagging material.

34. Raw materials Raw materials pose a major contamination threat to the product and the production environment, and warrant special attention from auditor. Untreated raw material of natural origin contain an extensive and varied microbial population, including potentially pathogenic organisms, such as E.coli and salmonella species. In case of excessively high bioburden, pre-treatment may be needed to reduce the bioburden to an acceptable level, using process such as heat filtration, irradiation, recrystallization from a biocidal solvent or where compatible ethylene oxide gas. Irrespective of the type raw material used, the auditor should confirm that the material is provided by an ‘approved ‘supplier.

35. Confidence in the suppliers manufacturing process and their quality system, which have been challenged through audit. likewise the sampling programmer used should be satisfactory based upon the nature of the raw material (natural/synthetic), the history and performance of the supplier, and end use of raw material. Sampling procedure should be reviewed. Reduce the risk of contamination both sample and bulk. Sampling equipment should be dedicated and clean. Samples should be properly trained in aseptic techniques. Warehouse storage condition should also be reviewed; temperature control should be satisfactory; pest control should be effective; and containers should be positioned so that they do not come into contact with damp; cold surfaces such as walls and floors.

36. Water Water is principle of raw material used in pharmaceutical industry. When reviewing water systems usually as part of a ‘product based audit', the auditor must establish quickly an understanding of the system and how it performs. Key facts to know include whether water is used directly manufacture ,and what's grades of water used. Management and operational issues include who owns the system, its complexity (one or multiple plants). A schematic of the system should be provided.

37. Packaging materials Cardboard, paperboard and pulpboard, unless sealed or treated, can provide a rich source of contamination, particularly moulds and gram positive bacteria, often as resistant spores. Materials become moist through poor storage ,levels of microbiological contamination can increase significantly. Material such as glass, synthetic rubbers, plastics and laminates have minimal surface microbial counts. However, if stored with limited protection in dusty or damp conditions and packed for transportation in cardboard boxes, often on damp ,dirty wooden pallets, they may contain moulds and bacterial spores.

38. Effective ventilation The aerial route of contamination is common and can be significantly reduced by an effective heating ventilation and air conditioning system. Humidity and Temperature control is important , since this not only provides a pleasant working environment, but also reduces the risk of mould contamination. Cleaning and disinfection Although routine sanitization of surfaces is key to controlling environmental contamination, its importance is often over looked. The sanitization programme and procedure should be reviewed to confirm the frequency and precise method of cleaning and their scientific basis.

39. The cleaning records should confirm procedural compliance (when, where, and by whom). The activity of any disinfectant used should be appropriate for the wide range of environmental contaminants likely to be present . The manufacturers instructions should be followed and fresh disinfectant solutions should be made up before use. Mops, sponges and cloths can provide an ideal environment for rapid and extensive growth of water-born organisms such as pseudomonas species. Inadequately stored and maintained cleaning equipment can be highly efficient vehicles for spreading micro-organisms throughout the environment.

40. References Quality assurance of pharmaceuticals, volume 2; second updated edition, world health organization, chapter:17, page no.: 54. Auditing of Microbiological Laboratory in Pharmaceutical Industry, International Journal of Pharmaceutical Research, Vol. 5, Issue 4 Feb 2020, ISSN-7693-32455 www.elsar.comaccessed on Nov.2011 Guidelines for quality and/or environmental management system auditing, 1st Edition, 2002 www.cityu.edu.hk, Internal Quality Audit Scheme. Handbook of microbiological quality control, edited by Rosamand M. Barid Norman A. Hodges and Stephen P. Denyer.

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