OK, maybe I'm beating a dead horse here, but it really annoys me. The prime directive is such a popular concept that it needs to be taken down a few notches, especially outside tge Star Trek universe where it at least was used as an occasional plot device. When I encounter people thinking it is actually a good ethical principle I get irritated.
The prime directive places the independent cultural development of a species higher than the welfare of its individual members (shades of "the needs of the many"?). While this sounds nice on paper, it has many nasty consequences. It means that the Federation should just look on when preventable disasters happen, even when inaction would be regarded as a moral outrage when occuring in respect to a non-protected culture.
Cultures may also be local. If the directive applies to the inhabitants of Zorgon XIII it ought to apply to indigenous peoples, not just preventing missionaries but also not giving them food, shelter and medicine if they need it.
If the directive is regarded as an ethical principle then it is presumably universal, and should also apply to the Federation. So the cultural development of the Federation is more valuable than the lives of any number of inhabitants. This way one gets a nice foundation for authoritarianism. It is easy to make the comparision with totalitarian Chinese policies seeking to safeguard 'social stability', but here the goal is even more nebulous and up for ruling technocrats to decide.
If it is not an universal principle, then the Federation just has it as a policy, habit or cultural decision. If another group like the Romulans wants to meddle it is OK, and the Federation can at most wring its hands or send warnings to the Romulans. If the Federation wants to be beneficient towards the protected culture it can use the meddlers as intermediaries (a bit like The Culture). This is of course total hypocricy and "not getting one's hands dirty".
If the directive only applies to every civilisation that is not sufficiently "adult", then one has to define what constitutes civilizational adulthood (in the Star Trek universe I guess spaceflight would be a likely definition, but as we have seen in enough episodes there appears to be bundles of spacefaring primitives out there). But if the value of independent cultures is so high as to merit the sacrifice of many individuals, then it appears likely that this value would be diminished by them getting adult and joining the interstellar community since the individual culture now would be subjected to globalization (OK, galactization).
The directive might be pragmatic in the sense that intervention brings disaster. In the IMHO rather silly novel Omega by Jack McDevitt everybody is firmly convinced that less developed civilizations will be totally culturally crushed by any contact with a more advanced one. This is said to be based on terrestrial experience, but as India and Japan show it is empirically not true. Even if it was true it does not seem to be a strong enough reason to avoid intervening against a threat against the survival of an entire alien species. In the novel what could have been a very straightforward rescue effort is turned inefficient and downright silly just to prevent any cultural contamination. But ethically, delaying/risking saving the inhabitants in order to ensure the survival of their culture is equivalent to first sending in rescuers to salvage all museums, libraries and archives, and once they are securely saved turning to the injured. It takes a very warped moral system to sustain that. And the assumption of this paragraph was that the directive was pragmatically based rather than a moral principle.
I agree with aristos Gabriel (spoiler) - if they got smallpox and I have a vaccine I'm going to give it to them, regardless of what they think. But I'm going to leave it up to them to think it. The authenticity of a culture comes from interacting with the outside universe (including other cultures), not from isolation. Respect for the uniqueness of cultures is an aesthetic value, but it is not strong enough to be an ethical value.