Julie Roberts Audit hot Topics and Regulatory Requirements
Overview Hot Topics Examples in warning letters Tips to detecting data integrity Recent changes in regulatory requirements
Hot Topics Microbial Control Strategy EM programme Risk Assessments Investigations Insufficient investigation RC not determined Data Integrity Recording of data Second person verification Chain of custody Maintaining compliance with Regulatory changes
Hot Topics - Microbial Control Strategy Overall philosophy for how you control microbial contamination for your processes. May need one per type of process e.g. aseptic fill vs terminal sterilisation vs non-sterile products Microbial control strategy demonstrates you understand your process, the limitations e.g. external materials/internal processes, what needs to be controlled, what can be measured, what cannot be measured
Hot Topics EM Programmes EM Programmes Written rationalisation for sample location i.e. risk assessment of activities Linkage to smoke studies Linkage to operational activities (not just at rest assessments) Periodic review of the applicability/relevance of the sampling programme Appropriate and useful review of data
Hot Topics - Investigations Insufficient investigation Not timely hard to resolve as time passes Assumptions made preventing a full investigation Investigation report does not document all investigation activities people so close they miss to document assumptions & thought processes
Hot Topics Common Audit Observations Trending of EM- insufficient, too narrow, % recovery rates not used Biological indicators D-value audits or on-site determination Cleaning validation maps indicating location of swabs/samples Counting of plates second person verification/ review of data/ accuracy of result
Hot Topics Common Audit Observations Trending of EM- insufficient, too narrow, % recovery rates not used Biological indicators D-value audits or on-site determination Cleaning validation maps indicating location of swabs/samples Counting of plates second person verification/ review of data/ accuracy of result
Hot topics within Microbiology pertaining to Data Integrity
Canada An FDA investigator observed your microbiologist reading an environmental monitoring (personnel) plate. The microbiologist reported the result for that plate as zero; however, our FDA investigator observed one (1) colony forming unit (CFU) on the plate. Your microbiologist corrected this observation on the form XX after the FDA investigator pointed it out to him. Your firm did not take further action to investigate and determine the impact of inaccurate reporting of your microbiological plate readings on the release of your batches. Your firm failed to record the incubation dates of the microbiological plates in the validation study of the (x) of (x) for (x) Solution (x) and (x) Spray.
China On March 2, 2015, we observed that all 14 culture media plates in incubator #6 were dried out and cracked, which compromised microbial growth promotion and accurate enumeration. These plates were used to test multiple API batches of (b)(4). You stated that tests for microbial limits were not routine for (b)(4). The microbiologist documented test methods and results when she had time, and there was a possibility that our QC microbiologist documents results by memory instead of document (sic) at time of operation.
India EM results sheets show X, Y and Z samples were taken on dates [x, y, z] however review of video recording for these periods do not show such samples being taken Your active air sampler samples 1000L of air taking 5.5mins, however video recording collection of this sample shows a sample time of <3mins. Since 2005, you have been using an un-validated and unqualified Agilent data acquisition unit (DAU) to monitor the temperature of the microbiological incubation rooms for media filled vials.
India Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers. Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had "forgotten" to document the details on the worksheet. The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.
Hot topics relating to Data Integrity & Data Compliance Chain of Custody Demonstration of chain of custody of EM plates WL in India/China showing fabrication of data Documented evidence for number of plates released to production, exposed, returned to lab, incubated, counted, destroyed Barcoding samples gives timing (exposure) also Logbooks can track Independence of personnel logging each stage
Hot topics relating to Data Integrity & Data Compliance Chain of custody (cont d) Ability to link each identification back to original plates Traceability of all activities Second person verification of counts What to verify? What to review?
Looking for Data Issues Notebooks, diaries, laboratory notebooks Drawers, cupboards, lockers amnesty review & clear out Review of data Are personnel trained to detect electronic edits (not just hand written edits)? Will your current reviews detect DI issues? What constitutes raw data? API strips?
Looking for Data Issues Equipment Controls around password/ number of licences available User access levels are they appropriate? Are they being shared? Who has more than one level of user access? Run a report of Admin log-on s check frequency Explore the Admin screen- what can be changed/ switched on/off? How many audit trails are available? Audit trails have a plan of what is reviewed, why its being reviewed, and how often you will review it.
Looking for Data issues Air samplers Can the sampling time be alerted/shortened? What data is the sampling machine retaining electronically (albeit transient) beyond your printout? EM programme Is your programme realistic for the number of staff? How long should it take someone to conduct all the EM required by your SOP? Are personnel completing it too quickly (same with Water Sampling)
Looking for Data issues Review electronic folders Do you have a policy or SOP for set up of electronic folders Check each system for atypical folder names/trial folders/project folders etc Check the waste basket on the pc when was it last emptied. What is in there?? Get IT to run activity reports from your various equipment for erroneous log-on s/ specific activity/ activity out of hours
Looking for Data issues Conduct random recounts of plates different days/ different personnel Review camera footage from production Operator behaviour EM & water sampler behaviour Cleaners
Hot topics Regulatory Updates and Changes
Regulatory Updates and Changes Demonstration of how you review updates to legislation Demonstration of review of applicability to your operations Implementation of the new guidance/requirements Sop to manage this process Evidence of change control to document the review, risk impact, and any changes required
Recent Regulatory Updates (courtesy Dr T Sandle) Production of WFI - Ph.Eur. Monograph 169 revised to include by a purification process that is equivalent to distillation. RO (single or double pass), coupled with other techniques such as EDI, UF or Nanofiltration is suitable http://www.ema.europa.eu/docs/en_gb/docum ent_library/scientific_guideline/2016/08/wc500 211657.pdf EMA Q&A provides clarification and guidance in the use of RO for manufacture of WFI, and to provide detailed guidance on the control of Biofilms
Regulatory Updates WHO draft guidance, Supplementary guidelines on Good Manufacturing Practices for Heating, Ventilation and Air-Conditioning Systems for Non-Sterile Pharmaceutical Dosage Forms. Scope of the document is: Solid dosage forms Covers other dosage forms (such as liquids, cream, ointments) and other classes of products including biological products, herbal medicines, complementary medicines and finishing process steps for APIs. Working document QAS/15.639/Rev.1, May 2016 http://www.who.int/medicines/areas/quality_safety/quality_assurance /HVAC_QAS15-639_31082015.pdf
Regulatory Updates EMA introduced a new draft guideline April 2016 "Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container. Steam sterilisation Dry heat sterilisation Ionisation radiation sterilisation Gas sterilisation Sterile filtration Aseptic processing http://www.ema.europa.eu/docs/en_gb/document_library/sc ientific_guideline/2016/04/wc500204724.pdf
Regulatory Updates ISO14644 Part 1 updated The standard is for classification and continued testing only. It does not replace EU GMP requirements and 0.5 and 5.0 µm need to be assessed. There is a new statistical approach for the selection of the number of particle locations and the evaluation of data collected. (number of locations generally increased) With particle counter locations, to align with GMP, the location should be orientated to the point of greatest risk e.g. close to fixed equipment.
Regulatory Updates USP <1116> December 2013 In the most critical areas within an aseptic processing operation, it is expected that less than 1% of the samples will yield any recoverable contamination. In the most advanced of modern aseptic operations that use separative technologies such as isolators or closed RABS, the recovery rate will approach zero at all times.
USP<1116> Table 3. Suggested Initial Contamination Recovery Rates in Aseptic Environments a. Room Classification Isolator/Closed RABS (ISO 5 or better) Active Air Sample (%) Settle Plate (9 cm) 4 h Exposure (%) Contact Plate or Swab (%) <0.1 <0.1 <0.1 <0.1 ISO 5 <1 <1 <1 <1 ISO 6 <3 <3 <3 <3 ISO 7 <5 <5 <5 <5 ISO 8 <10 <10 <10 <10 Glove or Garment (%) A All operators are aseptically gowned in these environments (with the exception of background environments for isolators). These recommendations do not apply to production areas for nonsterile products or other classified environments in which fully aseptic gowns are not donned. Detection frequency should be based on actual monitoring data and should be re-tabulated monthly. Action levels should be based on empirical process capability. If detection frequencies exceed the recommendations in Table 3 or are greater than established process capability, then corrective actions should be taken.
FDA Quality Metrics Initiative Jan 13 FDA Quality Metrics programme announced in Federal Register Notice (FRN) Jun 13 IPSE started Quality Metrics Initiative Dec 13 IPSE White paper delivered to FDA Jun-Nov 14 ISPE Wave 1 Jun 15 ISPE Wave 1 report issued Jul 15 FDA Request for Quality Metrics (Draft) Lot Acceptance Rate Product Quality Complaint Rate Invalidated Out-of-Specification (OOS) Rate Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate CAPA effectiveness & Process Capability & APR sign off
Regulatory Updates EU Annex 15 updated Oct 2015 GMP for Excipients - March 2016 EU GMP chapters 3 & 5 updated and effective March 2016 Guidance in Draft EU Annex 1 draft in discussion GMP for IMPs Final version to be published in April 2017 Date for coming into force likely October 2018 (with CTR) GMP for AT(I)MPs Public consultation recently closed; responses under assessment through October and November 2016
Preparing for the audit
Preparing for the audit Be honest with yourselves Where are the issues? Where are your weaknesses/ gaps in knowledge Any recurring issues from internal audits?
Preparing for the audit What is your timeline? You can t fix everything Determine what is important to you and prioritize If serious gaps cannot be addressed, look to capture them in your CAPA plan. Proof of intent is better than just intent
In Summary Be aware of current hot topics Be aware they can be inspector specific, agency specific! Ensure you are aware of recent changes to regulations and how they can impact you Don t let silly things catch you outcupboards/drawers/notebooks/passwords/poor compilation of validation folders Be confident - revise and know your own data & systems
Questions?