What Matters to Patients? QTPP for Vaccines: A-Vax Case Study

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Many of you asked for the QbD Risk Assessment Template for Vaccines. We are happy to announce that it is now available.

CMC-Vaccines Working Group published a QbD case study: A-VAX: Applying Quality by Design to Vaccines in 2012. The QTPP-CQA-CPP/CMA template is based on this A-Vax case study.

To make this a learning experience, I’d like to unveil the extraction process so that you can understand the granular steps behind the QbD case studies. During this process you can appreciate the effort that went into these case studies and more importantly, recognize some room for improvement.

Most importantly, I’m seeking your feedback on what QTPP should be.

Needless to say, we should take all case studies with grain of salt and not blindly copy them. We need to extract the principles and modify the strategy and tactics to our own projects.

For a QbD case study in Vaccines, A-VAX provides a detailed example. However, with any case study, there is room for improvement and I’d like to begin to go over a few with you.

So let’s begin with the first step – QbD Risk Assessment for A-VAX. This is just part 1.

(I’m traveling at this time so please bear with me as I catch up with my backlog of postings.)

 

QTPP = What Matters to Patients?

 

In ICH Q8,  QTPP is defined as “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.”

A-VAX first defines the QTPP (Quality Target Product Profile). QTPP should be the Product Description or Voice of Patients and Clinicians.

In current QbD case studies, QTPP typically equates to the Drug or Therapy Label. A-VAX is no exception.

A-VAX’s Target Product Profile (TPP) is a summary of its vaccine development program – only limited to labeling content. Later this table is extracted to QTPP.

 

Mechanism of Action	A-VAX (drug product) is a pentavalent vaccine containing the capsular Ps of X. horrificus serotypes 1-5, individually linked to a recombinant, non-infectious virus-like particle (VLP) and adjuvanted with an aluminum salt. A-VAX is expected to provide an enhanced cellular (Th1) and humoral (Th2), antigen-specific, protective immune response when compared with a natural X. horrificus infection.
Indication	A-VAX is indicated for the active immunization of 2-month-old to 60-month-old infants for prevention of cooties-related illnesses caused by X. horrificus
Primary Endpoints	70% reduction of X. horrificus-confirmed cooties disease within one year after dosing (below 60% is a no go) in the target population Safe and tolerable as defined by solicited symptoms, adverse events, and serious adverse events (no evidence of enhanced X. horrificus disease)
Key Claims	Has a favorable risk-benefit profile Can be dosed with other pediatric vaccines Universal recommendation except for premature infants (<36 weeks), immunocompromised infants, or infants with previous adverse reactions to A-VAX Achieves World Health Organization (WHO) stability requirements
Secondary Endpoints	Analysis supportive of primary endpoint in target population Reduction in X. horrificus-specific hospitalizations and emergency-room visits Reduction in X. horrificus-specific rates of bacteria-confirmed cooties disease Reduction in antibiotic use for X. horrificus-confirmed cooties disease Duration of protection >1 year (with/without booster)
Formulation/Dosing	Antigen and adjuvant in pre-filled syringe or single-dose vial Antigen and adjuvant containers are pre-mixed prior to injection 3 doses administered 2 months apart (preferably 0-, 2-, and 4-month pediatric vaccine schedule)
Approvals and Recommendations	Expecting Advisory Committee on Immunization Practices and other universal recommendations (i.e., United States, European Union, Canada, Japan, and WHO)

After the Phase 2 clinical trials data, the team defines the QTPP (Quality Target Product Profile).

Clinical results show an 87% response rate for each serotype. (Refer to Table 2-2: Assumed  Seroresponse Rates*) and reactogenicity profile (Table 2-3: Assumed Reactogenicity, Infant Stage*) for further details.

 

So the QTPP for A-Vax becomes:

 

Key Claims

Easy to administer, 0.5-mL subcutaneous delivery in a healthcare (outpatient) setting using a 1-mL syringe (27G  ½ inch needle) Stability: 2 years at room-temperature storage or 4 years at 2–8 °C, and 24 hours’ physical and chemical stability following reconstitution at 2–8 °C or 8 hours at room temperature (achieves WHO stability requirements) No animal- or human-derived products are used in the manufacture of A-VAX

Formulation/Dosing

Sterile product: the drug substance (Ps-VLP) can be sterile filtered 3 doses (containing 5 mcg each of Ps 1-4 and 50 mcg Ps 5; adsorbed to 300 mcg aluminum adjuvant as Ps-VLPs) administered 2 months apart (preferably 2, 4, and 6 months pediatric vaccine schedule) Lyophilized and reconstituted with standard diluents containing adjuvant: rapid reconstitution profile with viscosity of 1-3 cP Composition: sugar, surfactant, buffer (isotonic pH), and Ps-VLP conjugate Label volume 0.5 mL filled (actual fill volume will be greater than the label volume to account for losses) Single-dose vial (ISO2R vial, clear, Type I glass), latex-free stopper (13-mm coated stopper) and seal (13-mm aluminum seal with flip-off plastic button) Secondary packaging and shipping: allowed shipping-excursion temperature 2-40 °C for 3 days in a carton (10 vials/carton)

 

In the next article, I’ll write further on how A-VAX co-authors attempted to connect QTPP to CQA’s and CPP’s or CMA’s. While the effort was appreciated, the approach seemed disjointed and complex mainly because of the process-silo’ing approach.

Since I am a fan (like you) of the simple and lean approach to QbD Risk Assessment, I extracted all the information for our QbDWorks community.

 

You can get the QTPP-CQA-CPP/CMA template here. It took a fully-burdened 60 hours to go through the 381 pages, so I think you’ll save quite a lot of time and eye strain.

 

What Should (or not) be in QTPP?

 

During Pre-filled Syringe and Combination Products Conference, some folks asked,

“should we limit QTPP to only the drug label?”

“Aren’t we still in development mode, where we still have some room for other considerations such as the comfort of administration, or even business metrics? After all, other industries begin with “Voice of Customer” (Patient and Clinician in our case).”

For drug or therapy delivery QTPP’s, we could certainly add more patient-experience factors such as “ease or comfort of administration.”

Now I’m reaching out to you for your opinions. For those who are working with Vaccines, what should be in or out of the QTPP?