Ceph Lifesciences Private Limited — EU GMP NCR (EudraGMDP) Findings

During inspection, 28 deficiencies were identified, 4 of them has been classified as critical and 3 as major. The critical deficiencies are related to Quality Assurance management, aseptic operations in relation to compliance with Annex I of the GMP, maintenance and cleaning of equipment and facilities, and computerised systems. And the major deficiencies were observed in the areas to validation of analytical methods, staff training and batch release. Since the deficiencies found transversally affect both the manufacturing of non-sterile APIs (some of whose manufacturing facilities were also inspected) as well as sterile API facilities, it has been decided to issue an statement of Non-compliance with GMP that affects both types of products. The most relevant or critical deficiencies observed during the inspection are described below : - A number of severe violations of EU GMP Part II, EU GMP Annex 1 and Annex 11, potentially posing a risk to the quality of manufactured products and therefore to public health, demonstrated a lack of Quality Assurance oversight and understanding of core requirements. Significant shortcomings were observed across the GMP spectrum, documented as part of this inspection such as sterility assurance of APIs, cross contamination control, maintenance of facilities and equipment, computerised systems and training. - The company failed to implement core principles of EU GMP Annex 1 “Manufacture of Sterile Medicinal Products”. Consequently, the sterility of the Active Pharmaceutical Ingredients (API) manufactured in Block SE, Nectar Life Science Unit II, cannot be guaranteed, posing a risk to human and/or veterinary health. Abundant and important shortcomings were found among the site related to but not limited to site design, materials management, personnel behavior in aseptic areas, quality of exposed surfaces and failure to identify applicable requirements, risks and risk mitigation measures regarding revised Annex and general GMP requirements. -There is a significant risk of contamination/cross contamination of non-sterile APIs/intermediates manufactured based on the cleaning and/or maintenance status of the facility and the equipment used. Several observations made during the inspection of Oral Block F conclude that the manufacturing facilities and equipment for active ingredients have not been adequately maintained over the years, resulting in a significant deterioration of their condition and therefore posing a risk to the quality of APIs and ultimately to the patient. These observations include lack of maintenance, cleaning, presence of corrosion, concrete cracks, signs of liquid leakages, lack of hand-washing facilities, and other significant signs of poor maintenance, management and hygiene. - Several potential breaches on data integrity were found. Main aspects related to computerised systems were not addressed. The firm failed to implement basic requirements with regard to computerised systems as outlined in EU GMP Annex 11 and EU GMP Part II section 5.4ff. The flaws detected could potentially lead to failures in analytical testing and/or breaches in data integrity. The following shortcomings, among others, were observed: outdated operating systems on HPLC systems (Windows XP, Windows 7), no traceability (e.g. audit trail) or approval of the change of some HPLC sequences, problems with operators’ privileges and lack of computerised systems validation. - The Company also disregards pivotal aspects of GMP rules such as training (for instance, on the reviewed Annex I or failure to fulfill training requirements of the personnel), analytical method validation (not even planned to be done), or batch release verifications. Action taken/proposed by the NCA: Requested Variation of the marketing authorisation(s) This manufacturer should not be authorised in any new/ongoing marketing authorization or variation applications for the active pharmaceutical ingredients as long as the non-compliance statement is in force. The submission of a variation application for introducing alternative manufacturers of the active substances is recommended. Recall of batches already released The need of recall of released batches of finished products where APIs manufactured on this site have been used should be assessed by each NCA but based on the information gained during the inspection there is no cause to recommend a recall of concrete batches. Prohibition of supply Due to the nature of the non-compliance, prohibition of supply is recommended, unless there are no alternative suppliers or there is a risk of shortage. Suspension or voiding of CEP (action to be taken by EDQM) The EDQM Ad Hoc Committee has suspended all affected CEP manufactured in these facilities: a. CEP 2009-045, Cefuroxime axetil, amorphous b. CEP 2010-342, Ceftriaxone sodium, sterile c. CEP 2011-062, Cefuroxime sodium, sterile d. CEP 2011-226, Cefotaxime sodium, sterile e. CEP 2011-239, Cefixime f. CEP 2012-242, Cefepime dihydrochloride monohydrate, sterile g. CEP 2015-354, Cefpodoxime proxetil h. CEP 2016-170, Cefuroxime axetil, amorphous, Process-II i. CEP 2017-042, Cefixime, Process II j. CEP 2019-231, Ceftazidime pentahydrate with sodium carbonate for injection, sterile.