Warning letter / Medgel / July 2023 / Failure to test impurities, DEG&EG

Observation 3

Inadequate component identity testing and impurity testing of components used in drug product manufacture,

• Did not test all lots of Glycerin, Prolyne glycol, Sorbitol for Diethylene Glycol (DEG), Ethylene Glycol
• Accepted impurities in APIs as per supplier COA without performing testing of APIs, verifying / validating reliability of supplier COAs 

Response provided by the Firm to FDA is inadequate as it did not address risk assessment of products in market, interim plans for the products in market. Firm to perform independent assessment of material system, qualification of suppliers, adequacy of input material controls and establish remediation measures, provide procedures for supplier COA validation program and program for qualifying contract testing laboratories.

Contamination of Pharmaceutical ingredients like Glycerin, Propylene Glycol, Sorbitol, Mannitol etc with toxic contaminants like Diethylene Glycol (DEG) and Ethylene Glycol (EG) has been a major concern with all regulatory agencies. Several critical lethal poisoning incidents are reported due to high levels of Diethylene glycol (DEG), Ethylene glycol (EG) in drug products by different agencies including WHO, USFDA.

• Firms should implement procedures for sampling and testing of DEG and EG in Pharmaceutical ingredients & components with risk of DEG, EG impurities and contamination. USP (United States Pharmacopeia) monographs for Glycerin, Polyethylene Glycol and Sorbitol limits Diethylene glycol and Ethylene glycol to 0.1% each, by the Identification test B. FDA has also issued a new guidance on testing Glycerin and other high risk drug components for DEG and EG in May 2023. The guidance is applicable to all high risk components Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution.  (FDA Guidance on Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol).
• The test methods used shall be appropriately evaluated and verified as per ICH guidelines
• Firms should ensure they are using appropriate grades of the ingredients. Pharmaceutical ingredients like Glycerin, Propylene Glycol etc. has other major non pharmaceutical applications where the control of DEG / EG is not critical. There should be procedures to evaluate and qualify suppliers of Pharmaceutical components and ingredients. The evaluation shall verify the supplier’s control over the production, testing and control, storage and distribution of the ingredients, adequacy of quality system. Procedures shall be in place to prevent inadvertent receipt and use of the industrial grade solvents like Glycerin, Prolylene Glycol for Pharmaceutical Finished product application. (for example measures such as but not limited to-Supplier Qualification, Supplier Audit, Use of material in original containers with tamper proof seals, Material receipt verification checks, Sampling and testing of each container as defined in the USFDA guideline).

When Firms adopt Supplier/Vendor Certificate of Analysis (CoA) for approving materials it should be governed by adequate procedures. Procedure for Vendor Qualification & Approval shall evaluate the vendor quality systems and reliability to ensure quality and integrity of materials supplied. The Vendor Qualification shall involve testing of initial samples (prior to commercial delivery), and testing of initial lots supplied for full specifications. After this, once confidence is built on the supplies and supplier, a reduced testing procedure may be implemented, for accepting materials based on Vendor CoA. Criteria for implementing a reduced testing procedure should be defined and implemented – e.g. no failure or rejection of supplies made, comparable test results for parameters between the supplier and the Firm, audit / review of the supplier’s Quality system, controls in place to deliver material conforming to quality and integrity each time. Also perform a risk assessment, identify any additional measures required before implementing a reduced testing programme for each material. When adopting a reduced testing procedure, not all parameters shall be skipped from testing – at least one specific identity test shall be performed on each container; and critical parameters, toxic impurities which can cause catastrophic consequence shall be tested in every consignment. There should also be a procedure for periodic evaluation, when materials will be tested for full specifications at predefined frequency like for example– every 5^th or 10^th consignment. And if any OOS / failures are observed during such periodic testing all the lots from previous consignments become suspect and should be tested; Adequate reserve samples should be retained for all lots of pharmaceutical components – APIs, Ingredients, primary packing materials for such investigation.

 When Firms use contract testing facilities, they shall be evaluated and qualified. The qualification should include an audit and evaluation of the Quality systems and GMP compliance of the testing facility. Agreements should be established between the Firm and the Testing facility clearly delineating roles and responsibilities. The testing facilities should also be available for audits by regulatory agencies, whenever required.

Also refer the post:

USFDA Warning letters, 483s, WHO Alerts on Diethylene Glycol (DEG), Ethylene Glycol (EG) contamination in Drug Products (Pharmaplast Egypt; Champaklal, India and others).

• Where Firms were using components like Propylene Glycol, Glycerine, Sorbitol at high risk of DEG / EG impurities and contaminants and Firm was not testing each lot of the input material, develop a comprehensive corrective action plan to evaluate and mitigate the risks:
  • Review all the batches /products within expiry, identify the batch / lot numbers of ingredients used. If reserve / control samples of the ingredients are in available, initiate testing of the same for DEG / EG contaminants. If the levels of contaminants are observed to be higher than the limits, all corresponding finished good batches shall be recalled.
  • If control samples / reserve samples of ingredients are not available, work out a priority plan for testing all the finished product batches reserve samples. For deciding priorities, take up testing of current lots of the ingredients. If the values for DEG / EG are observed to be close to or higher than the limit, all the finished product batches which has these ingredients / ingredients from the same supplier shall be tested in priority. Develop a logical plan for testing of the finished product batches – For each lot of input material, 1-2 lots of finished products where the ingredient was used shall be tested. If the test shows higher DEG / EG content, all other lots of finished good lot manufactured with same lot of ingredients shall be recalled.
  • For those ingredients / sources where DEG / EG content are well below the specified limits in the current lots, a reduced testing approach can be adopted on the finished product (say 30% of batches to be tested first, selecting 1-2 finished product lots for each lot of input ingredient) and if no failures are observed further testing may not be warranted. But if any failures are observed in the set of samples selected, all the finished product batches with these ingredients shall also be tested and accordingly recalls initiated.
• Make an assessment of reduced testing procedure followed by the Firm across all other input materials and components – whether reduced testing procedure adopted is supported by qualification of the material / source through inhouse testing followed by periodic testing. If not evaluate the current lots of the material in inventory for those parameters which are not tested. For mitigating the risks, a similar approach for testing of reserve samples of ingredients, finished products as described above shall be adopted.
• Perform a reassessment of each material and its suppler(s) for status of qualification, reliability, integrity and safety of supply chain, material controls and quality system compliance. Take remediation actions – requalification to address gaps, delisting suppliers who don’t qualify.
• Enhance the procedure for reduced testing of input materials – addressing supplier qualification, evaluation of qualification samples and initial lots, CoA validation by matching test results by the Firm and vendor, periodic evaluation with defined frequency, testing of critical parameters in all lots and risk assessment to support reduced testing.