Simplification of EU/UK drug product batch release process

                                                                 - Ganadhish Kamat

As per Annex 16 of EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, each lot of drug product has to go through QP release process in EU. Similar procedure exists in UK. As per this guideline QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force in the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP). For the batches manufactured outside EU/UK, apart from above requirement, QP has to ensure that storage conditions have been maintained during transportation and each batch has to be fully tested in a Member state. After the prescribed timeline in Brexit agreement, separate testing will be required in UK and EU. Of course while QP is responsible for the batch release, overall responsibility of ensuring quality and compliance lies with Marketing Authorization Holder.

It has been well accepted fact that quality of the product cannot be assured by testing but same has to be built in the design and assured by implementing appropriate controls in the manufacturing process. So, the major steps contributing to the quality of the drug product are Product development and manufacturing (including packaging). ICH Q8 (QbD) and current guideline on Process validation require that all the variables related to materials and process are well understood and appropriate control strategy is established during design stage to ensure quality of the product throughout the shelf-life. The adequacy of these controls and the capability of the process is verified during process performance qualification stage.  Continued process verification ensures that process remains within control throughout the product lifecycle. Manufacturing process also involves various in-process checks and monitoring steps to assure that the process steps remain under control throughout the batch. With all these controls in place, the end product testing which is performed on a small sample taken from the batch is mere formality to confirm that the product meets the specification. Level of assurance provided by such testing is quite insignificant because of the small sample size used in various tests irrespective of the batch sizes which can be as high as few million units. Sample sizes for different tests performed on the drug product are indicated below –

·        Assay (content of drug in the product) – 10 to 20 units

·        Uniformity of dosage form – 10 units

·        Dissolution rate – 6 units

·        Related substances – Powder equivalent to 1- 5 units

·        Sterility testing – 20 units

Out of the above tests, least assurance is provided by sterility test. For instance, if a batch of 10,000 units has 10 non-sterile units, there is 98% probability that batch will pass the sterility test.

In spite of all these limitations in the end product testing and in spite of the fact that each batch is tested by the manufacturer prior to release, performing the testing again in EU member state is a non-value adding step. Apart from the testing cost, it results in delay of release of batches anywhere from 15days to few months after the shipment reaches EU/UK. The testing cost per batch ranges from around 1500 Euros to 4000 Euros per batch depending upon the type of the product and the test involved. Apart from the batch testing cost, there is significant amount of set up cost related to analytical method transfer, supply of standards, columns etc. All these costs get added to the cost of medicines and are finally borne by the patients without getting any additional benefit.

When EMEA / MHRA can trust manufactures to perform major quality contributing steps of development and manufacturing, there is no reason not to trust them for minor step of end product testing. EMEA / MHRA perform periodic audits of all the manufacturing sites and these audits cover the review of laboratory systems and controls. With implementation of Annex 11 requirements in the QC laboratories, there is high level of assurance about the analytical results generated by the manufacturer and there is no reason not to believe them when all other data related to development and manufacturing is believed. It may be noted that India exports medicines to countries all over the world, with nearly 50% exports going to USA. No other countries have such requirement of testing each batch before release.

The requirement of performing testing in member state might have been put in place earlier due to absence of mature quality systems, lack of good distribution systems and lack of controls like Annex 11. Now with improvement is all these aspects time has come to eliminate this non-value adding step in QP release so that citizens in EU & UK can get faster access to high quality medicines at lower cost.