Regulatory: FDA Exempts Phase 1 drugs from Part211

A couple of weeks (15-July) ago the FDA issued Docket FDA-2005-N-0170-0005. This lays out their decision to exempt Phase 1 investigational drugs from the requirements of Part211;

(c) An investigational drug for use in a phase 1 study, as described in
§ 312.21(a) of this chapter, is subject to the statutory requirements set forth in
21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance
with the regulations in part 211 of this chapter. However, this exemption does
not apply to an investigational drug for use in a phase 1 study once the
investigational drug has been made available for use by or for the sponsor
in a phase 2 or phase 3 study, as described in § 312.21(b) and (c) of this
chapter, or the drug has been lawfully marketed. If the investigational drug has
been made available in a phase 2 or phase 3 study or the drug has been
lawfully marketed, the drug for use in the phase 1 study must comply with
part 211.

Now here's what confuses me. In the preamble to this, the FDA state:

FDA believes this change...is appropriate because many of the issues
presented by the production of investigational drugs intended for use
in the relatively small phase 1 clinical trials are different from
issues presented by the production of drug products for
use in the larger phase 2 and phase 3 clinical trials or for commercial
marketing.

OK, so far so good, that makes sense...

Additionally, many of the specific requirements in the regulations in part
211 do not apply to the conditions under which many drugs for use in
phase 1 clinical trials are produced. For example, the concerns underlying the
regulations’ requirement for fully validated manufacturing processes,
rotation of the stock for drug product containers, the repackaging and
relabeling of drug products, and separate packaging and production areas
are generally not concerns for these very limited production investigational drug
products used in phase 1 clinical trials.

So this is a nice, clear rationale for exempting these types of drugs; risk-based and scientific.

BUT then they throw in a caveat...

However, once an investigational drug product has been manufactured by, or for,
a sponsor and is available for use in a phase 2 or phase 3 study, thus demonstrating
an intent to expose more subjects to the investigational drug and requiring that
the regulations’ CGMP requirements be met, the same investigational drug
product used in any subsequent phase 1 study by the same sponsor must be
manufactured in compliance with part 211.

So, you scale up production for Phase 2/3 and apply Part211 processes and controls, fine. But then if you decide to return to do a second Phase 1 trial, all those good reasons for not applying Part 211 cease to be valid!? How does that work? Surely, if I scrap a Phase 2 trial and want to repeat Phase 1 (for whatever reason) there exist the same, risk-based, scientific reasons for exempting the drug, i.e. small batches, stock rotation not feasible, repackaging and relabelling?
And then to top it all off, this only applies to when the same Sponsor does it. Meaning Sponsor A does Phase 1 under an IND, then does a Phase 2 under Part 211, then goes and does Phase 1 again, but this time has to still apply Part 211. Subsequently, along comes Sponsor B with the same drug, doing Phase 1 but only using an IND. OK, if the drug is commercially marketed and then goes through a Phase 1 trial for another indication, apply Part211 since the drug samples for trial will be just taken from the commercial stock, no problems.

So much for clarity. I have read most of the preamble and cannot see either a comment pointing out this scenario or any explanation of why the FDA have made the rule this way. So I must be missing something very obvious...let me know if you can see why a Phase 1 drug should be treated any differently before or after it has passed through another Phase.

The European Compliance Academy also reports on this here.

Regulatory: FDA Proposed rule shot down

Towards the end of 2007, the FDA issued the proposed rule "Amendment to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals".

You can see the proposed rule, comments and subsequent withdrawal notice here.

I commented (as did a number of other companies) in a response to the FDA as follows:

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GENERAL COMMENT

The Agency's provision of clarification in this area is to be welcomed, but the proposed ruling has a potential to conflict with current industry practice and curb the development of good practice contrary to ASTM E2500 .

Specifically, we question the approach expressed in the proposed change to 211.103 and 211.188.

These changes are intended to “clarify the agency's longstanding interpretation of, or increase latitude for manufacturers in complying with, preexisting CGMP requirements”. In our opinion they do not achieve this goal, but rather confuse the agency’s intent with respect to the requirements of 211.68.

The agency states in the preamble (Section II. D);

“we are amending Sec. 211.101(c) and (d), 211.103, 211.182, and 211.188(b)(11) to indicate that the use of automated equipment under Sec. 211.68 may eliminate the need for verification by a second individual”

However the proposed changes will still require verification by a second individual, with the first “individual” being an automated system.

Our understanding of this proposed change is that if a calculation of yield is performed by an automated (computer) system, then that calculation must also be verified manually (211.103). The person manually verifying the calculation must then be identified in the batch records for that operation (211.188).

Currently, under direction from predicate rules such as 211.68(b), if an automated (computer) system were employed to calculate yield, that function would be validated. The rationale for appropriately validating the function is that the function can be proven to be accurate and consistent and therefore negate the need for manual verification. In effect, the manual verification is appropriately performed during the validation exercise (using a range of test data and positive and negative test cases), thus ensuring future accurate operation in a controlled system.

Under current good practice this means that a manufacturer will spend time and resource in validating an automated function (such as yield calculation) knowing that during subsequent operation they can be confident of a consistently accurate output given accurate inputs, and therefore that output does not need to be re-checked manually. This has an operational time/cost benefit that is a major incentive for a manufacturer to invest in the initial validation effort.

We believe that although such calculations potentially impact product quality and patient safety, the use of appropriately validated computerized systems is in line with ASTM E2500 which places the emphasis on the appropriate verification of systems.

However, the proposed change subverts this paradigm and puts into question the value of validating such functions. In essence, pharmaceutical manufacturers may question the benefit of validating a function that must additionally be manually verified every time it operates?

Our concern is that pharmaceutical manufacturers are required to expend time and effort in the validation of the automated system but will no longer have the benefit of improved process efficiency and operational cost saving.

Additionally, given that “this proposed rule represents the first increment of modifications to parts 210 and 211”, we are concerned that similar changes might be considered for other sections where an automated system may be used to perform a function.

We believe that a pragmatic approach would encompass validation of the automated system (as required in 211.68(b)) and that other rules such as 211.103 would require a verification of data entry and/or resulting output e.g. the second person should verify that the input data and validated result is included in, for example, the batch record, but would not be required to recalculate the result so long as this has been performed by an appropriately validated system.

We believe this would reflect the current understanding and practices within the industry and the intent by the agency to “encourage innovation and the development of improved manufacturing technologies”.

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Most companies who responded presented similar arguments. However, it is worth noting that some companies actually welcomed the proposed ruling as a good thing(!) that clarified the situation. It is not clear if they actually read the proposed rule, or just wanted to get their names on the FDA website as a respondent.