How Comparability Protocols, ICH Q12 Established Conditions, and PACMPs Lower FDA Post-Approval Reporting Categories

How comparability protocols, ICH Q12 established conditions, and PACMPs lower post-approval reporting categories

FDA offers sponsors three related ways to move a future chemistry, manufacturing, and controls (CMC) change into a lower reporting category than the default. Each one asks the sponsor to agree on the evidence with FDA in advance, before the change is made:

• Comparability protocols (CPs): FDA approves a prospective plan for a defined change. When the change is later carried out and meets the plan's criteria, it is reported in the category the protocol specifies.
• Post-approval change management protocols (PACMPs): the ICH Q12 term for the same mechanism. FDA treats it as synonymous with a CP.
• Established conditions (ECs): under ICH Q12, the application states which CMC elements are legally binding and what reporting category applies to changes in each. Under Q12, changes to elements that are not ECs are managed in the pharmaceutical quality system (PQS) and do not require a regulatory submission.

In every case the lower category is conditional. It holds only if the agreed studies are performed and the predefined acceptance criteria are met.

The baseline: default reporting categories

FDA sets the default reporting category by the change's potential to adversely affect identity, strength, quality, purity, or potency as they relate to safety or effectiveness. Whether testing later shows an actual adverse effect does not set the category ²⁶⁰.

Every tool covered below works by moving a change down this ladder. Most often that means PAS to CBE-30, CBE-30 to CBE-0, or a supplement to an annual report.

Comparability protocols

What a CP does

FDA's final guidance Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA defines a CP as an FDA-approved, prospective plan for evaluating specified future CMC changes. An approved CP can justify reporting a change in a lower category than would otherwise apply. The reduction is not automatic: the approved CP states the category, and the sponsor must perform the protocol's activities and meet its predefined acceptance criteria ⁶⁷. CVM's GFI #156, written for new animal drugs, gives examples of PAS dropping to CBE-30, CBE, or annual report. It says the usual reduction is one category, although PAS to annual report may sometimes be possible ⁶⁸.

Submission and content

• Where to submit: a CP can go in the original application or in a PAS. In a PAS, the cover letter should name "Comparability Protocol" as its subject ⁶⁹.
• Level of detail: the protocol should be a detailed implementation plan. It needs enough detail for FDA to judge both the change and the reduced category being proposed ⁷¹.
• Required elements: the protocol specifies the change, the tests and studies, the analytical procedures, and the acceptance criteria that will show whether the change harms the product ⁷².
• Additional elements recommended by CVM GFI #156: the type and amount of data to be reported, a proposed reporting category for FDA's agreement, what happens if equivalence or the criteria are not met, and a commitment to update or withdraw the protocol once it is obsolete ⁷³⁷⁴⁷⁵.

Scope and limits

Changes a CP can cover. A CP can cover changes to the drug substance, drug product, production process, quality controls, equipment, or facilities, including changes that would normally need a PAS. Repetitive changes are especially good candidates ^381382383. A single CP can cover one or several BLAs, and one change or several related changes ³⁸⁴. CVM recommends separate protocols for changes that are not related to each other ³⁸⁵.

Changes generally unsuitable for a CP. These include changes with high or uncertain risk to quality, and changes whose effects can only be judged with nonclinical, PK/PD, or clinical safety or efficacy data ³⁸¹³⁸⁶. Even when a CP can be written, FDA may be unable to assign any category other than PAS for some changes ³⁸⁸.

Conditions on implementation. FDA must approve the CP before any change is implemented under it ⁷⁶. Each change is then submitted in the designated category along with the specified results, deviations, and investigations ⁷⁷. If the acceptance criteria are not met, the sponsor cannot distribute product made under the CP, and the reduced category no longer applies ⁷⁸⁶⁷.

ICH Q12: established conditions and the PLCM document

Established conditions

FDA has adopted Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. Q12 defines ECs as the legally binding information in an application that is needed to assure product quality, so a change to an EC requires a regulatory submission. Everything else in the application is supportive information, and changing it does not require a submission ²²³²²⁴.

• Identifying ECs: the sponsor states which elements it proposes as ECs and gives its rationale in the relevant CTD modules. Q12 does not require product-specific ECs unless a regulation does ²²⁵.
• Assigning categories: the sponsor justifies a proposed reporting category for future changes to each EC, using a risk-based approach informed by product knowledge ^227228229.
• What happens to non-EC changes: all CMC changes go through the PQS, but only changes to ECs also have to be reported to FDA ²³².
• Non-EC changes in BLAs: FDA guidance on annual-report changes for specified biological products says application information that is not an EC can be changed without a supplement or an annual-report entry ²³⁴.

US mapping and legal basis

FDA's draft guidance ICH Q12: Implementation Considerations for FDA-Regulated Products links the EC concept to 21 CFR 314.70(a)(1)(i) and 601.12(a)(1). Those regulations do not define ECs, but they set up a risk-based approach to reporting changes ¹²³. The draft maps the Q12 categories to US submission types as follows ²³⁰²³¹:

How more knowledge leads to fewer or lower-category ECs

Q12's annexes show three ways to set ECs for a manufacturing process, and they can be combined within one application ³⁹². In the powder-blending example:

The principle behind the annexes is that more product and process knowledge reduces uncertainty. That can show a parameter does not need to be an EC, or justify moving a change in a critical process parameter from prior approval to notification. In-line tests that control quality stay ECs ³⁹⁸.

The PLCM document

The Product Lifecycle Management (PLCM) document collects in one place the ECs, the reporting category for each, any PACMPs, and any post-approval CMC commitments. It is updated over the product lifecycle ³²⁰³²¹. FDA's draft implementation guidance recommends submitting it in tabular form in eCTD section 3.2.R ³²²³²³.

PACMPs: the Q12 version of a CP

Under Q12, a PACMP is a protocol the regulator approves in advance. It sets out how a commercial-phase CMC change will be prepared, assessed, and reported, and the conditions and acceptance criteria that must be met before the change is implemented ²⁷⁵. It works in two steps:

1. Approval of the protocol. The sponsor describes the change, its risk-management activities, the planned studies and acceptance criteria, and a proposed reporting category. FDA approves the protocol before it is carried out ²⁷⁶.
2. Execution and reporting. The sponsor runs the studies and, if the criteria are met, reports the results in the agreed category. If the criteria are not met, the PACMP route is not available ²⁷⁷.

Agreeing on the evidence ahead of time can support a lower reporting category, a shorter review, or both. If a review before implementation finds that the risk has gone up, the previously approved category no longer applies ²⁷⁸²⁷⁹. FDA's CP guidance states that a CP is synonymous with a Q12 PACMP. After a change is successfully implemented, it is reported in the category given in the approved CP, under 314.70 or 601.12 ^140141142.

Examples from approved applications

Site additions and site changes: PAS to CBE-30

Adding or changing a manufacturing site is the most common subject of CPs in Drugs@FDA review records.

• Calquence (NDA 216387): a CP for adding alternative drug-substance and drug-product manufacturing and testing facilities that had not yet been identified, proposed as CBE-30. All review disciplines found the proposed post-approval changes acceptable ³⁴.
• Horizant (NDA 022399): CPs for site changes covering drug-substance manufacture and testing, and drug-product packaging and testing, reported as CBE-30. The protocol for changing the drug-product manufacturing site was removed ³⁵.
• Byvalson (NDA 206302): changes or additions of drug-substance sites qualify for CBE-30 only if the proposed site is cGMP-compliant for the intended operation at the time of submission ³⁶.
• Idvynso (NDA 216964): CBE-30 protocols for a drug-substance equipment change and for adding a drug-product manufacturing facility ³⁸.
• Ryzodeg 70/30 (application 203313): a CBE-30 protocol for adding manufacturing sites for the FlexTouch prefilled pen device, which FDA found acceptable ³⁹.
• Veklury (NDA 214787): a PACMP proposing CBE-30 for alternative drug-substance manufacturing sites, conditional on acceptable cGMP status. The review record retrieved does not state whether it was finally approved ¹¹⁵.

Formulation and packaging changes

• Lybrel (NDA 021864): FDA agreed to a CP under which replacing or deleting the tablet wax polish would be reported as CBE-30 instead of in a PAS ³⁷.
• Itovebi (NDA 219249): a CP to reduce the bottle count from 30 to 28 tablets, without changing the bottle, so the package matches the 28-day dosing cycle. Genentech plans to submit the change as a CBE-0. FDA judged it reasonable and low risk and found the protocol, the labeling change, and the supporting data acceptable ^114310311.

Biologics: protocols that allow annual-report reporting

BLA quality assessments list several protocols that allow annual-report reporting for changes that would otherwise need a supplement:

• Elahere (BLA 761310): CPs for new product introductions for both the antibody and the drug substance, reported in the annual report ³⁰²³⁰³.
• Rybrevant (BLA 761210): protocols for introducing new products at two facilities, and a drug-product shelf-life extension protocol based on full shelf-life data from three commercial-scale batches. All are reported in the annual report ^304363364.
• Lamzede (BLA 761278): annual-report protocols for qualifying new working cell banks, retesting cell banks, a TFF membrane lifetime study, qualifying and requalifying the reference standard, and stability updates ³⁰⁵³⁰⁶.
• Wyost/Jubbonti (BLA 761362): a PLCM document with ECs and reporting categories for the drug-substance process. The approved protocols include annual stability protocols and new-product-introduction protocols for the drug-substance, vial, and prefilled-syringe facilities ^312194195.

Shelf-life extension under an approved stability protocol

Many NDAs and BLAs include commitments that let the sponsor extend expiration dating through the annual report, provided long-term data meet the approved stability protocol. FDA attaches conditions:

• Myfortic (NDA 050791): FDA required satisfactory long-term data from at least three production batches. An extension based on pilot-scale batches would need a PAS ³⁵³.
• Keytruda (BLA 125514): an extension must rest on real-time data from the approved protocol, and those data can be submitted in an annual report ³⁵⁸.
• Repatha (BLA 125522), pre-BLA minutes: FDA said a protocol approved with the BLA would allow per-protocol extensions with annual-report notification. The drug-product protocol should cover the full combination device ³⁶⁰³⁶¹.

These routes have limits. For TissueBlue, further extension requires a PAS. For Ventolin HFA, removing a restriction on annual-report extensions requires a PAS ³⁶⁷³⁶⁸.

Established conditions accepted in recent NDAs

Recent quality assessments show ECs being proposed and evaluated in NDAs:

When FDA does not grant the reduction

FDA does not always agree to the proposed category:

• Movantik (NDA 204760): FDA found the CP for new drug-substance manufacturing sites unacceptable, so those changes require a PAS ¹¹⁷.
• Caprelsa (NDA 022405): the sponsor agreed to change its site-change protocol from CBE-0 to CBE-30 ¹¹⁶.

These outcomes are consistent with FDA's guidance. CVM's animal-drug CP guidance describes a one-category reduction as usual, and site changes that may need a cGMP inspection are harder to justify under a CP ⁶⁸³⁸⁷.

Practical takeaways

• Pick the right tool. Use a CP or PACMP for a specific, foreseeable change, such as a site addition, a working cell bank, or a shelf-life extension. Use ECs and a PLCM document to set the reporting framework for the whole product. The two can be combined, as in Itovebi and Wyost/Jubbonti ^309312194.
• Justify larger drops carefully. CVM's animal-drug guidance describes a one-category reduction as usual ⁶⁸, although the BLA protocols above show larger reductions to annual report are accepted with strong supporting data.
• Build in conditions. Conditions such as cGMP status of the new site, commercial-scale batches, and three-batch real-time stability data appear repeatedly in FDA's agreements ^36115353.
• Show your development knowledge. Under Q12, enhanced or performance-based development knowledge is what justifies fewer ECs or lower categories ^395396398.
• Keep the reduction alive. It survives only if the sponsor meets the protocol's acceptance criteria and the risk picture has not changed by the time of implementation ⁶⁷²⁷⁹.