ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements

ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements (TM/HS) CLASSIFICATION OF GMP NONCONFORMANCE Prepared by: Malaysia & Indonesia Approved by: ASEAN TMHS GMP Task Force Endorsed by: ASEAN TMHS Product Working Group 1

OUTLINES Introduction Interpretation Example of Deficiencies Regulatory Actions Example of Writing Deficiencies: Good and Bad ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 2

INTRODUCTION Classification of GMP non-conformance is very crucial during conducting of an inspection and writing the inspection report. Classification of GMP non-conformance will facilitate company to take the necessary CAPA while the number or type of GMP nonconformance will determine the rating of GMP inspection by NRA. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 3

DEFICIENCIES Critical Major Minor Others ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 4

CRITICAL DEFICIENCY A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal. A critical deficiency also occurs when it is observed that the manufacturer has engaged in fraud, misinterpretation or falsification of products or data. May consist of several related deficiencies, none of which on its own may be critical, but which may together represent a critical deficiency or systems failure and should be explained and reported as such. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 5

MAJOR DEFICIENCY A deficiency that is not a critical deficiency which has produced or may produce a product, which does not comply with its marketing authorisation; OR does not ensure effective implementation of the required GMP control measures; OR indicates a major deviation from the terms of the marketing authorisation; ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 6

MAJOR DEFICIENCY OR indicates a failure to carry out satisfactory procedures for release of batches or (within PIC/S) a failure of the authorised person to fulfil his/her required duties; OR consist of several “other” related deficiencies, none of which on its own may be major, but which may together represent a major deficiency or systems failure and should be explained and reported as such. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 7

OTHER DEFICIENCY/ MINOR A deficiency which cannot be classified as either critical or major, but which indicates a departure from good manufacturing practice. (A deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as major or critical) ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 8

COMMENT One-off minor departures from GMP are usually not formally considered deficiencies, but are brought to the attention of the manufacturer as comments. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 9

EXAMPLES OF CRITICAL DEFICIENCIES Evident of gross pest infestation No Master Batch Documents Absence, intentional falsification or misinterpretation of manufacturing and packaging records Failure to ensure the quality and/or identity of starting materials No evidence that mandated recall processes have been complied with ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 10

EXAMPLES OF MAJOR DEFICIENCIES No or grossly inadequate air filtration to minimize airborne contaminants Cleaning program not followed and evidence of dirty premises/ equipment or non-verified cleaning procedures Damaged to walls/ceilings in manufacturing areas where product is exposed Design of manufacturing area that does not permit effective cleaning ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 11

EXAMPLES OF MAJOR DEFICIENCIES (cont.) Insufficient manufacturing space that could lead to mix-ups No raw material sampling area Stored equipment not protected from contamination Inadequate initial/ on-going and/or training records Cleaning procedures not documented and/or no records ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 12

EXAMPLES OF MAJOR DEFICIENCIES (cont.) Deviations from instructions not approved Inadequate internal inspection program No proper release for supply procedure Product rework without proper approval Insufficient lighting in production or inspection areas The temperature of critical temperature controlled storage areas not monitored and alarmed ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 13

UPGRADING INITIAL CLASSIFICATION A major or other deficiency may be upgraded by one level to either critical or major deficiency when conditions may exist to satisfy the intent of the definition for the upgraded risk classification. Include: Repeat or recurring deficiencies Grouping or combination of deficiencies Product Risk Failure of a manufacturer’s management to identify and take prudent measures to reduce consumer risk to an acceptable level for product distributed and future production from a deficient practice or process. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 14

DOWNGRADING INITIAL CLASSIFICATION A major or other deficiency may be downgraded by one level to either major or other deficiency when conditions may exist to satisfy the intent of the definition for the downgraded risk classification. Include: Minimising product risk Minimising risk of patient harm Action taken by the manufacturer e.g. CAPA plan to reduce the risk of the deficiency ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 15

REGULATORY ACTIONS FOLLOWING CRITICAL OR MAJOR DEFICIENCIES Compliance and enforcement measures are dependent upon a number of factors including: significance of violations such as critical deficiency and large numbers of major deficiencies, history of the site, potential risks to products and assessment of the manufacturer’s proposed corrective actions. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 16

REGULATORY ACTIONS FOLLOWING CRITICAL OR MAJOR DEFICIENCIES If the findings are linked to patient safety, immediate action needs to be taken. Factors that can be considered include: The risk to health and safety; Compliance history of the manufacturer; Whether the manufacturer acted with indifference or premeditation; The degree of cooperation offered; The likelihood that the same problem will reoccur; The likelihood of the enforcement action being effective ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 17

REGULATORY ACTIONS FOLLOWING CRITICAL OR MAJOR DEFICIENCIES Actions that can be taken may include: Compliance related communications which alert the manufacturer to the regulatory authority’s concern, and possibility for future regulatory action if remedial action is not effective Regulatory action against the site authorisation or GMP approval (refusal, suspension or amendment of an establishment licence) Market action such as recall (voluntary or mandated by regulatory authority) ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 18

REGULATORY ACTIONS FOLLOWING CRITICAL OR MAJOR DEFICIENCIES Actions that can be taken may include (cont.): Prohibition of supply/ importation Prosecution Communications to the public using public warning/ public advisory or information updates; Suspension or cancellation of Marketing Authorisation/Product Licence Health product label or changes ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 19

EXAMPLE: WRITING DEFICIENCY The requirement of Clause XXX that cross contamination should be avoided by appropriate technical or organizational measures were not fully met as evidenced by: o The purified water hose not hung to drain. o The opening to the manometer on the ceiling had been covered with adhesive tape. o The lid of stainless steel container YYY showed adhesive tape remainder and tack welding resulting in the lid difficult to clean. o Seals on the drum washer were in poor condition. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 20

POORLY CONSTRUCTED, GROUPED OR INCORRECT WRITTEN DEFICIENCIES Poor format and lack of clarity Taking it beyond code requirements Lack of clarity and detail Inappropriate or wrong clauses Overstating Incorrect grouping and inappropriate claused referred Repetition – two different deficiencies merged into one Over-emphasis ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 21

EXAMPLE: LACK OF CLARITY & DETAIL The requirements of clause 4.WW on effective cleaning of product contact equipment were not met. Further there was a lack of traceability of cleaning through records. For example: a) The cleaning of sampling tools was not documented in a procedure b) The cleaning procedures were not always consistent with regards to the time specified before the resanitation of equipment. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 22

EXAMPLE: REPETITION The requirements of clauses 3.AA, 3.BB, 5.CC, 5.DD regarding cleaning were not always met. The following matters were noted. a) Cleaning agents were inadequately labelled to indicate their status. b) There was a dirty wire brush in the clean equipment room. c) Clean equipment was stored on dirty metal shelves. d) A cupboard adjacent to the wash-bay contained insect sprays, unlabelled containers of wash liquids, dirty cleaning equipment and miscellanous junk. e) Spray containers observed in several areas, which were said to contain 70% ethanol, were not properly labelled. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 23

EXAMPLE: OVER EMPHASIS The requirements of clause 3.YY and 3.ZZ relating to calibration of equipment had not been met as several calibrations had not been completed: a) Temperature and humidity recorders had not been calibrated b) Calibration due dates have passed on some balances. c) Pressure testing equipment was out of calibration date and did not have a warning sign. ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 24

REFERENCES PIC/S GUIDANCE ON CLASSIFICATION OF DEFICIENCIES (DRAFT; JUNE 2016) PIC/S INSPECTION REPORT FORMAT; PI 013-3; 25 SEPTEMBER 2007 NPRA PROCEDURE FOR PREPARING A GMP INSPECTION REPORT : PKP/200/309 ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 25

ASEAN Guidelines on GMP for Traditional Medicines / Health Supplements - 2015 Classification of GMP Non-Conformance 26