On November 8th, Inovatie Serviços em Saúde held a webinar on opportunities and challenges in the post-registration of medicines, presented by Claudia Cilento, a biochemical pharmacist graduated from the University of São Paulo, with a postgraduate degree in Administration and Marketing from the Escola Superior de Advertising and Marketing (ESPM), master's degree from the Faculty of Public Health at USP, managing partner and responsible for the Regulatory Affairs area at Inovatie.
Claudia began her presentation by saying that the post-registration of a medicine often brings more challenges than an initial registration because, as the entire production and quality control process is connected, an apparently simple change can impact other important parameters, causing other changes. The manufacture of a medicine is a dynamic process, where all steps are interconnected, and it is not, for example, feasible to change an excipient without revisiting the analytical method or the degradation product.
And this difficulty can be even greater when it comes to post-registration for an older product, as it is not always possible to obtain all the information necessary to compare what was approved versus what was proposed.
Claudia also mentioned on the additional difficulties the situation where medicines are manufactured outside the country due to possible differences in legislation, classification of change, and technical documents that need to be presented.
The post-registration of the clinical part, such as a new indication or a new dosage, tends to be a simpler process from a technical point of view, as there is no impact on the production process, however, it is also necessary to complete several steps, such as carry out a clinical study, structure the entire process and send it for approval by the National Health Surveillance Agency (ANVISA).
Optimal flow for post-registration
Claudia explained that the demand for post-registration generally arises from a real need for improvement and, ideally, the professional who identified this need should request a change control meeting to discuss the proposed change where several factors will be evaluated.
This is the planning phase so that the team can discuss the proposal, evaluate the impact, frame the change and check what evidence is necessary to prove that the product will maintain the same quality, safety and effectiveness, as the central point that must permeate the entire the evaluation of any post-registration is to ensure that the proposed changes do not impact the performance of the medicine. Only after these considerations will it be decided whether the proposal will move forward, or not.
Claudia highlighted an important point in this process, which is to define the type of approach that the company will adopt: whether it will follow the list of evidence required by ANVISA or whether it will opt for a risk assessment approach where the company defends the classification as lower risk and proposes the evidence that must be presented.
Once the post-registration process is approved by change control, the tests are carried out, the evidence is attached that will guarantee that the product will not undergo changes and the documentation is forwarded for evaluation by the Regulatory department. Once in compliance, the next step is to send it for evaluation by ANVISA.
Challenges
Claudia highlighted that the main challenge of post-registration is classification, which raises many doubts, due to the different possibilities presented, in addition to filling out the Company's Technical Assessment Report (PATE), which requires a lot of attention. According to her, the ideal is for the professionals who complete it to have in-depth knowledge of the product, the process and the change being requested so that the assessment is adequate.
The time for post-registration approval depends on the classification and can, in some cases, take up to a year.
Claudia also spoke about some specific cases that can bring greater complexity to the process, such as, for example, the change in the Active Pharmaceutical Ingredient (API) where, in addition to the evaluation and classification of the change in the API, the impact on the medicine must be evaluated. For example, if there is a change in the manufacturing location of the API and there are no changes to the process, ANVISA must only be notified, but if there is a change in the process or synthesis route, it may even be necessary to change the analytical method and specification in the finished product. Another factor that makes the API post-registration even more complex is that there are products with and without an Active Pharmaceutical Ingredient Dossier Adequacy Letter (APIDAL), with different adequacy rules.
But she warned that, no matter how complex a post-registration process is, under no circumstances should a medicine be marketed without post-registration being approved, as the company would be committing a health infraction.
Finally, she mentioned what is fundamental for creating a successful post-registration: knowing the product, its critical quality attributes and expected performance; classify it appropriately and evaluate the evidence that needs to be forwarded to ANVISA that will guarantee that the product's performance will be maintained.
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