A Compilation of WHO GMP Audit Points

Transcription

1 A Compilation of WHO GMP Audit Points Collected from WHOPIR of 28 companies Part VIII of VIII Current article Part VIII Support QMS Prepared and Submitted By: Edited by : A. Jwalakanth B.Pharm, MBA (Aus) Student Diploma In GMP XIII th batch Insights Professional Management Academy, PUNE Atul Shirgaonkar Course Director Diploma In GMP Insights Professional Management Academy, PUNE

2 SUPPORT QMS Out of Specification Test Results Retraining was effected and recorded OOS results were evaluated and investigated in accordance with written procedure. OOS was closed within 30 days The procedure follows the conventional approach with sections on tracing assignable cause to laboratory error or production error. Details on sampling and re-sampling were given Selected reports were reviewed. In all cases the established cause was analyst s error The SOP on "Handling and investigation of out of specification (OOS) results plus the corresponding flow chart and the registers were reviewed OOS log for 2010: There was separate registration for raw materials, packaging materials, finished products and stability study. OOS results were evaluated and investigated in accordance with written procedure. OOS was closed within 30 days OOS results were evaluated and investigated in accordance with SOP"OOS investigation for raw material, finished product & stability study". OOS investigation flow chart and Check list were available. Time limit for closing out of OOS was specified - 30 calendar days Technology Transfer: Transfer of Technology was included in the change control programme. The transfer of one of the products one plant to other plant was well documented in a Change Control. Deviations: Deviations related to the production were documented in Batch Manufacturing Reports/Batch Packaging Reports (BMR/BPR). According with the SOP QA personnel checked the deviation and decided that either a full scale product failure investigation must be performed Deviation was defined as unplanned departure from an approved instruction or established standard or an unexpected observation Deviations were investigated on Risk based analysis Deviations were classified as planned and unplanned. Deviations were closed within 30 days. Deviations were trended monthly and yearly SOP for handling Deviations SOP on:"deviation handling". Deviations were classified as: 1. Planned deviation 2. Unplanned deviation 3. Major deviation 4. Minor deviation The deviations registers were reviewed to verify that all deviations were included in the PQR. The deviation report for the change in packaging location was inspected. The SOP for deviations didn't address trending of deviations, to identify areas of recurrent deviations for continuous improvement in identifying possible corrective actions to be taken to prevent recurrent deviations. Page 2 of 11

3 DEVIATION MANAGEMENT: Deviation management was described in sop Deviations were investigated in accordance with the check list Deviations were classified into three CR, MJ, MI Deviations were trended yearly Changes and deviations were listed in PQR Deviations and changes should be closed in 30 DAYS The source of API was listed in the PQR for export market, the source of packing material, and packing material specification numbers were not listed in PQR Deviation management was described in a written SOP and flow chart SOP for handling Deviations Deviations and related SOP & Registers according to year wise There were sections on impact analysis, retraining, trends, CAPAs. Close out was required within 7 days for a major incident and 15 for a minor Deviation on action to address drains that were found without water air-seal Trending of deviations A formal system for deviation management was described in writing. Deviations were re-corded also in the Manufacturing Instruction Records (MIR) and Packaging Instruction Re-cords (PIR). Deviations were classified as planned and unplanned. Deviations were closed within 30 days. Deviations were trended monthly and yearly Changes and deviations were listed in Annual Product Review, TRENDS were part of APR Deviations were recorded in Batch Manufacturing records (BMR) and Batch Packaging Records (BPR). Trending of deviations was carried out every six months. Deviation trends and Log bookwere reviewed and found to be satisfactory. SOP on Handling of Deviations. The selected examples reviewed included: Process validation: The prospective validation protocol/report for specific product was reviewed. The V blender was used for the original validation studies but was not available in Block F, however equivalent equipment for blending and tablet compression was available in Block F and used for manufacture. The certificate of equivalence of tablet compression machine and Equipment Equivalency protocol for tablet compression machines as well as Certificate of equivalence of V blenders and Equipment Equivalency protocol for V blender ere therefore reviewed and found to acceptable. The process validation report for specific product was also reviewed and the results indicated low RSD results indicating good reproducibility The source data were reviewed (chromatograms) and back calculations from the peak areas were checked for selected samples Validation was carried out for three batches manufactured for the local market. PERFORMACNE QUALIFICATION OR PROCESS VALIDATION BOTH ARE TREATED AS SAME There was a validation matrix for the key processes, systems and major equipment Process validation reports and links to batch documents Page 3 of 11

4 Process validation source data (samples, chromatograms) Assay (FPP): Specification reference was BP. BP method is potentiometric titration (BP 2010) while In-house method was HPLC method. The method was similar to the Ethambutol hydrochloride tablets assay according with USP 32 monograph. A protocol and report were reviewed briefly for the process validation. Focus was placed on key steps and stages of the production process, and source data. Source data were verified for the blending stage. Chromatograms and calculations were checked including electronically stored data. According to the source data, the %RSD should have been calculated but it was not. The sample analysis of Rifampicin took place over 16 hours. Hold time of Rifampicin samples was inspected as the company analysed samples over an extended period despite the recommendations in the USP. Pest control: There was a pest control system in operation and elaborated in an SOP. The service was Contracted to an outside company and a Technical Agreement were available. All visits were recorded and observations noted. The schedule included routine regular spraying Insectocutors was checked twice daily. Glue pads used to trap rodents were regularly checked and changed every three months SOP for preparation and use of Disinfectants (It specifies the preparation, concentration, validity (48 Hours) and rotation of disinfectants. Records of preparation of disinfectants were reviewed) Insect and rodent control procedure Didn't clearly identify the exact location of glue mates in receiving bay and warehouse area The location and frequency of the type of control used to be was defined. Measures used included Insectocutors, rodent baits and glue pads Pest control was managed by an outside contractor following a procedure, if defined location and frequency of the type of control used for insects (Fortnightly) and for rodents (fortnightly) There were insectocutor installation were managed using an SOP, these installation were the only internally placed pest controls allowed Self inspection procedures: This procedure was comprehensive and the check list used covered all areas of production, quality control, quality assurance and engineering Self inspection was carried out once in three months for all departments according to a written SOP and audit schedule. Audits were carried out by suitable trained, independent personnel from those departments what were subjects for audits The SOP for self inspection, together the plan and the report of implementation SOP on Self Inspection, Plans, Reports SOP on Self Inspection, Plans, Reports Self inspection was carried out every 6 months. Self inspection team was properly trained. Self inspection observations were classified as critical, major and minor After completion of self inspection, the self inspection report was drawn up and necessary CAPA were initiated. After the completion of CAPA the self inspection was closed out Observations were classified as three cr, mj, mi Self inspection schedule must be prepared The company had a basic self inspection program which consisted of semi-annual reviews Page 4 of 11

5 of all of its operations, and production activities. There was a standard operating procedure to cover the basic approach to self inspection, and an annexed set of checklists designed to cover different manufacturing activities in different areas. SELF INSPECTION AND QUALIT AUDIT: Self inspection was performed routinely, twice per year according to a written procedure. Reports were prepared and corrective actions were required. Proposed corrective actions were reviewed and approved. Implementation of corrective actions was controlled Self-inspection was documented, and there was an effective follow-up programme. Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines was not be permitted in production, laboratory and storage areas, or in any Other areas where they might adversely influence product quality Questionnaires on GMP requirements and main GMP items were covered. After completion of self inspection, self inspection report was drawn up and necessary Corrective and preventive actions (CAPA's) were initiated. Implementation of CAPA s was monitored. Self inspection schedule was available for inspection. Self inspection was carried out every 6 months. Self inspection team was properly trained. Self inspection observations were classified as critical, major and minor regular continuous SOP training. Self inspection were carried out twice a year according to department wise Personnel administration features included: Training: Recruitment and training of personnel Safety Medical examination organization Laundry The induction training planner was given by the Human Resource department and other individual departments established their annual department training plans The company had had a comprehensive training program for all the employees. This was coordinated by QA but the concerned department head identified the training was identified based on experience, qualification, job assigned Attendance sheets for training sessions were available Training was of two types: 1. Basic Training: general discipline basics of GMP, Hygiene & Sanitization Safety entry/exit procedures 2. In-service training: Operating instruction of production machines, Job related Training (SOPs Training), maintenance of BMRs and GLP training Training evaluation was carried out by questionnaires, oral and written examinations and detailed audits of work performance. Retraining needs were identified through performance evaluation. Records of both Training as well as retraining was maintained Records maintained included Personnel Training Card and Training Log Book. Page 5 of 11

6 Effectiveness of Training was assessed by: TRAINING: Immediate evaluation of the personnel which was conducted after each training session by Questionnaire or by oral assessment. Long-term evaluation which was carried out by the concerned supervisor and training Coordinator. The concerned department head identified the retraining needs of the employees Based on their consecutive assessment and audit deficiencies. Any change in system or Procedures requires retraining Training (Induction and continuing), SOP plus records of Training for selected personnel Provision for trending of observations from self inspection reports The quality of the systems, procedures and products were regularly reviewed and monitored through an elaborate self inspection procedure and annual product review. New staff was given an orientation to the company and its Products and underwent basic training including health, hygiene and safety regulations, basics of GMP and statutory requirements. In-service training included operating instruction of production machines, Job related Training(SOPs Training), maintenance of BMRs and GLP training Retraining needs were identified through performance reviews, self-inspection and audits. Self inspection Corresponding correction reports Reports were provided to management for evaluation there was trending was observed Training records were maintained together with personnel files The overall training approach was specified in a written SOP. A training needs matrix was set up for each employee The attendance sheets for specified training were available. Training is to be given on-job training, external training, and continuous training, and training of new and revised procedures Training flow chart, training plan and program me for the year wise has to be prepared Training record on risk assessment (FMEA) for two employees The training needs were identified and training was organized as per SOP "Procedure for training of plant personnel". There were several types of training explained in the SOP. Training effectiveness was evaluated by the questions and multiple choice or True or False answers. SOP "Procedure for training and certification of analyst" was reviewed. For the analysts certification "Coded samples" were given to analyst and results were Compared against a key. Analyst's re-certification was carried out for all analysts once in two years Induction training is given to all staff by HR, and then introduced to all departments. A schedule is defined for the induction. On the job training is given; retraining is given as Needed and a certificate is issued after successful training. Assessment is done (generally) by questionnaire. Training needs are identified and a training schedule is defined. Training is given and assessment is done. Provision is made for re-training Induction training covers personnel, GMP, engineering, health and safety, security; QA etc. The training program for 2010 was reviewed. The records for February 2010 (including trainees) were requested. Several training records were reviewed. The training records revealed that the topics identified for training were covered. Questionnaires were in place for assessment after training in topics such as cgmp. Page 6 of 11

7 Training was done according to an annual schedule. The company had a comprehensive training program for all the employees. Training was divided into FIVE categories: 1. Induction 2. C GMP 3. CGLP 4. Job related SOP Training 5. Safety Health and Environment and specific Training Training certificates were issued after successful completion of training. If training was not successful, personnel had to be re-trained and re-evaluation had to be carried out. Persons engaged in manufacturing and QC operations had received comprehensive initial Training (induction programme) and on the job training covering their operational duties and GMP. Effectiveness of training was examined by written exam, but there was need to effectively monitor compliance with the policy on pass mark and retraining The concerned department head identified the training needs based on their assessment and job assigned to the employees Training procedures and records Training Information Management System was being used to schedule, record and evaluate the training needs Effectiveness of Training was assessed by: Immediate evaluation of the personnel which was conducted after each training session by questionnaire and oral assessment, retraining was given if the score was less than 70% Training of production officer who performed IPC counting of tablets Questionnaire that was used to assess the training of a production officer on FMEA Long-term evaluation which was carried out by the concerned supervisor and training coordinator. All employees were evaluated once in 6 months The concerned department head identified the retraining needs of the employees based on their consecutive assessment and audit deficiencies personnel receiving training should be supervised until they were trained in their respective areas The training programme for casual staff NOTE: Any change in the system or Procedure requires retraining PRODUCT RECALLS: The timelines to conclude the recalls (Class I within 2 days, Class II within 7 days and Class III within 15 days), composition of the recall committee and the parties to be informed while conducting a recall. SOP for Product Recall System accordingly year wise SOP for Product Recall System accordingly year wise In case there are no recalls, a mock recall should be carried out every three years according to the company SOP Training records and annual training plan were maintained Recall procedure was reviewed. Responsible person for the recall was Corporate QA. Corporate QA afterwards informed Unit QA Composition of the recall committee and the parties to be informed while conducting a recall Page 7 of 11

8 There was a procedure to conduct dummy recall at least once every two years in order to evaluate the effectiveness of the recall procedure Dummy recall validation report was reviewed and it covered only the domestic market. There were three recall levels specified: Level A Recall from the customers Level B Recall from all links in the distribution chain Level C Recall from certain links in the distribution chain Dummy recall Validation protocol/report "Dummy recall validation" was available for inspection and was found to be satisfactory. According with SOP Dummy recall should be revalidation once in two years if there was no recalls Recall was classified as CLASS 1, CLASS 2, and CLASS 3 and there is time limit according to class EX: CLASS 2 AND 3 is three business days Compliant Handling: Compliant Handling system (SOP + Registers for year wise) compliant register compliant investigation report sop for complaints: the sop detailed the procedure for handling, investigation, reporting and corrective action NOTE: The sop has to mention, if complaint of serious nature it has to report to national authority SOP for root cause analysis related to a complaint; There was a procedure for handling complaints. This ensured that complaints were registered, Investigated, corrective action was taken and feedback was given. This procedure was covered by an SOP The Responsible person for coordinating and processing the complaints was designated. Complaint investigation records were kept together with corresponding BMR. CAPAs were identified Ishikawa fish bone tool was used for the 95% of complaint investigation Complaints were classified as following: Complaints were classified as product quality complaints, product packaging complaints and medical complaints. Complaints were categorized as category I, II and III. Complaints were reviewed every 3 months A. Product Quality complains - category I B. Product packaging complaint - category II C. Medical complaints Category III. Serious medical complaints were reported to respective RA) Market complaint registers for 2008 and 2010 were checked and found acceptable The recall procedure was explained in the SOP "Product recall procedure" and the responsible person for handling of the recalls was QA Executive / Manager Complaints were categorized as: quality complaints, packaging complaints and adverse drug event complaints. Complaint trending was carried out every three months In case of the quality complaints other batches were checked in order to determine whether they are also affected Page 8 of 11

9 COMPLIANTS: Complaints were classified as Critical / Major / Minor and others were recorded in the complaint log books and market complaint list CAPA was generated for all critical and major complaints in accordance with written SOP The compliant investigation was completed within 30 days and if necessary a decision about recall will be taken according to SOP The investigation report of market complaints for specific products and trend analysis of market compliant and market compliant analysis for year wise reviewed Complaints has to be investigate according to ROOT CAUSE ANALYSIS, and SUITABLE CAPA were determined A matrix was available for the product complaint investigation referring to BMR, BPR review, analytical record review etc.. The inspectors reviewed complaint number XYZ Complaints: selected examples reviewed with no major issues. A complaint received by WHO-PQ related to the poor sealing of blisters of one product was presented to the company for investigation and an acknowledgement letter was received Complaints were categorized as category I, II and III. Complaints were reviewed every 3 months In case of the quality complaints other batches were checked in order to determine whether they are also affected Trending of Complaints: Complaint trending will be done once per year. COMPLIANT HANDLING PROCEDURE : The SOP on handling market complaints was reviewed. Complaints were classified as critical, major, minor and Adverse Drug Reaction The register for 2010 was issued by QA and included a complaint submitted by WHO about wrinkled blisters of Ethambutol/Isoniazid/Pyrazinamide/Rifampicin tablets 275/75/400/150mg. This was reviewed in detail covering BMR; vendor audit of the supplier of foil; sampling and testing of foil; storage, issuance and use of foils; in-process checks during packaging; the investigation report. A number of observations were made: a) It was noted that packaging was done using 6 rolls of leftover Aluminium foil, instead of 1 roll usually used. 3 out of the 9 PVC/PVDC rolls were also leftovers, significantly smaller than the normal full roll. b) There were no specific checks whenever a roll was changed and correct setting of the tension and alignment of the foil was only manually checked; no copy of the blister after change was kept with the BMR; frequency of leak test performed was not enough to capture problems during change of rolls. c) In leak test done for the blisters, the vacuum actually achieved was not systematically monitored or recorded. d) At the time, "wrinkling of blisters" was not listed among defects to look for during inspection of blisters and there was no SOP on AQL levels. A new SOP on AQL has been put in place listing wrinkling of a blister as minor defect, without assessing its possible indication of poor sealing leading to leakage. Page 9 of 11

10 d) These risks in packaging and inadequate in-process checks were not considered during investigation. It was therefore concluded that the weakness noted in the packaging, in-process testing and investigation could not give confidence that adequate QA procedures were in place during manufacturing. Holding time studies of cleaned equipment: MB analysis was performed to establish clean equipment holding time Audit report was written and corrective actions (CA) proposed. Implementation of CA was checked by the QA. SOP on the hold time for dispensed raw materials, in-process and finished. SOP on Hold time study and the following selected reports of hold time study protocols and Reports: a) Protocol for Binder holds time study. b) Protocol for Lubricated blends hold time study. c) Protocol for the Compressed tablets hold time study. d) Protocol and Report for blend hold time for one ARV product Protocol and Report for blend hold time for one ARV product conducted Holding time validation for granules and tablets According with validation report the holding time for granules was specified 45 days and for coated tablets 90 days. Holding time in between blending and compression was defined. There was a general SOP on Cleaning and storage and labeling of cleaned equipment. It specified the holding time for wrapped items to be 72 hours and unwrapped items to be 24 hours Holding time studies of cleaned equipment Validation report was reviewed. Holding time studies for the sifter was evaluated. According with validation protocol/report samples were taken every day for duration of 9 days Samples were taken using swab method. MB analysis was performed. Acceptance limit for microorganisms was specified. According with the results established holding time for cleaned equipment was specified 7 days. Calibration of Balances: Daily checking of analytical balances was carried out using two calibrated standard weights, fortnightly calibration was carried out using 6 calibrated standard weights,. Standard weights calibration certificates were presented to the inspectors It was discussed with the company that it would be necessary to specify on the label "clean before use" in case if the cleaning hold time has been exceeded. Production equipment and instrument calibration schedule and PM schedule were managed Page 10 of 11

11 by the SAP system Schedules to be Prepared: Equipment re-qualification schedule Preventive maintenance schedule for facilities and equipment Self inspection and schedule Stability study, annual stability schedule and monthly stability planner Various documents were reviewed such as: Layout of the site Organogram Quality Manual Change control SOP Different change control forms Lists of all products manufactured, with their marketing destination SOP for Annual Report Annual report for Forcan-150 (year 2008) Stability studies for particular product Daily checking of balances: Daily checking of analytical balances was carried out using 5 different calibrated Standard weights; monthly calibration was carried out using 11 weights. Standard Weights calibration certificates were presented to inspectors. Computer System: The company were requested to provide documentation to show that the system had been Validated and was operated in accordance with guidelines given in both the WHO GMP Publication and EU Orange Guide Page 11 of 11