Common deficiencies/ hot topics

Transcription

1 Common deficiencies/ hot topics Non-sterile & API manufacture Oisín Daly GMP Conference 7 February 2017 Dublin

2 Non-sterile finished product manufacture

3 Deficiencies by Eudralex Vol. 4 GMP guide > 60% 3

4 Focus of Non-Sterile content 1. Documentation 2. Investigation handling & root cause analysis 3. Updates to Chapters 3 & 5 4. Examples of common deficiencies 4

5 Documentation Practices not in line with procedures Operation X was observed and this was contrary to what was described in the approved procedure. Procedures not detailed enough Procedure X did not adequately describe the process of reviewing chromatographic raw data and the individual checks involved. Logbooks contemporaneous recording The logbook for X machine was issued one week after the machine had been operated. 5

6 Other documentation related deficiencies Qualification & Validation Outsourced Activities 6

7 Documentation Qualification & Validation >40% 7

8 Documentation Outsourced Activities Technical Agreements Not in place Agreements were not in place with a number of service providers. Not detailed enough responsibilities regarding the assessment of deviations were not defined. 06/02/2017 8

9 Documentation Chapter 4 (Documentation) is the most cited Chapter of the EU Guide to GMP Key message: EASY TO ADDRESS! 9

10 Investigation Handling & Root Cause Analysis 36% 10

11 Investigation Handling & Root Cause Analysis Chapter 1, Paragraph 1.4 (xiv) Appropriate level of root cause analysis applied to investigations Quality Risk Management principles Consider most likely root cause if not confirmed Human error must be justified CAPAs with effectiveness checks 11

12 Investigation Handling & Root Cause Analysis Deviation X related to logo erosion and tablet wetting problems as a result of a spray gun blockage during coating; No rationale was documented for discarding 5 of 7 potential root causes identified in the investigation; Assigning human error as the root cause due to an operator s mistake during gun calibration was not considered appropriate given that the procedure was followed correctly; There was no CAPA implemented as a result of this deviation. 06/02/

13 Investigation Handling & Root Cause Analysis Deviation Y related to a low OOS assay result the root cause identified that the batch was filled at the lower end of the validated fill weight limit; lack of justification as to why the lower limit remained appropriate, and the corrective action was to instruct operators to run the batch at target or above; lack of justification as to why previous batches were not affected, no review had been performed of the average weights/ IPC weights recorded for previous batches. 13

14 Investigation Handling & Root Cause Analysis Key message: Ensure all aspects of investigation are considered and documented Root cause analysis tools and templates Issue isolated or not? CAPA implemented 14

15 Updates to GMP Guide Chapters 3 and 5 Cross contamination requirements Toxicological evaluation (ref. EU guidance document on setting health based exposure limits) QRM. With respect to new product introduction X,.. there was no risk assessment performed to determine the risk posed to the other products manufactured in the same equipment, what segregation was required and what were the acceptable levels for cleaning. 15

16 Updates to GMP Guide Chapter 5 Supplier Qualification QRM Qualification of API supplier X was deficient in that the 5 year audit frequency was not supported through application of QRM. Key Message: Changes have come into effect, ensure systems are in line with new requirements 06/02/

17 Other common deficiencies Product Quality Reviews PQRs were put together on the basis of different customers there was no requirement to review PQRs together that would identify issues or trends that would apply to the process or product as a whole Production There was no requirement to check or document the integrity of the sieve screen post use in the dry additive dispensing area 17

18 Other common deficiencies Packaging operations & control There were no provisions in place to ensure bottles were clean prior to filling No internal reference number was issued for each batch of printed components received 18

19 API manufacture

20 Focus of API content Documentation Investigations handling Examples of common deficiencies Similar findings in relation to nonsterile products! 20

21 API deficiencies Premises & Equipment Oil was observed leaking from the agitator unit on vessel X Pipework in room X was not labelled with contents and direction of flow Materials management The manufacturers addresses for all GMP related materials were not included on SAP or the approved suppliers list 21

22 API deficiencies Cleaning validation The definition of a dirty hold time was not considered justified in that there was no specified maximum time between the completion of processing and completion of equipment cleaning. Visual inspection of the cleaned equipment was relied upon during cleaning validation when no rinse or swab samples were to be taken. There was no study performed to demonstrate that residues representing the maximum carryover limit could be seen visually. 22

23 API deficiencies Water Out of specification results for microbiological testing and total organic carbon of the reverse osmosis water used for final stage manufacture and equipment cleaning had not been investigated or documented in a timely manner. There was no periodic microbiological monitoring or endotoxin testing of purified water. Production During the review of batch record X, it was observed that critical steps in the manufacture were not witnessed or subject to an equivalent control. 06/02/

24 Questions