Gap Analysis: CMO and Sponsor Relationship

EJ Brandreth

Inovio Pharmaceuticals

Inherent Challenges

CMO must manage many clients; each one wants to be the top priority, each has their own concept of current GMP compliance

A CMO operates on a set profit; a Sponsor may operate on huge profits; Sponsor resources can be unlimited

A Sponsor product team manages one product or platform; the CMO must manage dozens of products concurrently

Inherent Challenges

CMO must make overall compliance of the entire facility the top priority; each client insists that their product, and compliance needs, is the top priority

CMO Quality must manage directions from the FDA, QPs, auditors, sales, consultants.

CMO must be an extension of Sponsor’s quality system, but can’t host all clients at once

In an Ideal World… The CMO and client would partner together in a

relationship of mutual respect, transparency and support for each other…

The Agency could rely on the noble, altruistic instincts of industry to do the right thing at all times; to trust the human compassion of corporate leaders to put compliance and patient safety first …

Managing Expectations Level of compliance influenced by clinical needs; a

deviation may be minor to one client (can’t miss the

trial start date) and may be completely unacceptable to

another client (no urgent need for the material)

Example: 7 % reject level for routine, cullable visible

particles, when the average (UCL) is 3%

Managing Expectations Phase – appropriate GMPs requires a lot of

interpretation, individual judgment

A Phase I Biologic is very different than an ANDA stage

Generic; the Generic has an enormously larger amount

of relevant historical safety and efficacy data based on

the innovator molecule.

Safety Consequences

Level of Quality

Levels of Quality Small Start Up Large Biotech

Risk Assessments Informal, based on Criticality

Formal RA Teams, all process steps, all programs have a RA

Specifications FIO, wide specs Strict, clear limits, stat-based alert/action/reject limits

Investigations Focused, lot based, QA driven

Platform-based, horizontal/vertical, multidisciplinary

Vendor Control C of A, reputation only

Audits, 3 lots independently tested

Training Job-specific Job-specific, plus technical, regulatory, quality. Broad-based

Client Profiles Small Biotech

Midsize Industry Giant High Profile

Industry Giant Low Profile

Level of Compliance

Low-Med High High Low

Depth of Experience

Low Med High High

Flexibility High Med Low High

Embrace Risk High Med Low High

Matches and Mismatches Small Start-Up Biotech, Clinical

Midsize Biotech

Industry Giant High Quality

Industry Giant Low Quality

Phase I, II CMO

Perfect Ok No Client rejects CMO

Heck No Client bullies CMO

Phase III CMO Yes Yes Yes No Client bullies CMO

Commercial CMO

No CMO rejects client

Ok Yes Yes

Large Commercial CMO

No CMO rejects client

Ok Perfect Yes

Sponsor Selects CMO

Sponsor Audits CMO

QAG Completed

Mfg starts

Ideal Timeline

Sponsor Selects CMO

Mfg starts

Quality Notified

Audit

Completed

Crisis (common) Timeline

Gaps - CMO’s do not have complete visibility to product history; must rely on

(biased) direction of Sponsor. API is delivered to CMO without CMO’s confirmation of its history; source, quality of tests, facility of origin, age, precipitation, deviations, etc.

- CMO’s have no control/visibility over final distribution (Sponsor’s eventual use of finished material; Phase 1 or commercial?) - CMO’s rely on Sponsor’s directives (Accept “at risk”, ship “at risk” )

- Sponsor may have a unique agreement with Agency, but CMO is held

to general cGMP expectations (Unique agreements between Reviewer and Sponsor not always in line with Field Inspector expectations )

Gaps Client insists API is sterile, and demands that you not

sample it before filling

(CMO should have an SOP which requires in-house bioburden prior to exposure to aseptic suite; protect the facility at all times) (QAG also should stipulate that CMO has final decision on incoming requirements)

Gaps Product is provided with little handling safety data.

MSDS is not complete, but sponsor promises it to be

perfectly safe; “None of our technicians seem to have

any problems with it”

Solution: CMO insists on a Safebridge rating

Case Study- Vial Haze A lot of vials was received with a visible residue, placed on

hold by CMO.

Vendor explains residue is ammonium sulfate, and is intentionally left on vials, and washes off easily. Common practice for over 30 years; dealkalyzing the internal surface.

CMO notes that a slight haze is still visible on a few vials after washing.

During FDA inspection, further investigation is requested, and product made with these vials are voluntarily placed on hold.

A study is initiated to evaluate the haze observed.

Case Study- Vial Haze One client is commercial, and agrees with approach.

Another client is clinical, and has a study about to begin, and cannot have a delay in study initiation.

Clinical client refuses to agree to place lots on hold; insists ammonium sulfate residue would be safe, requests CMO contact FDA inspector to set up a 3 way call.

FDA tells CMO to adhere with commitments made during inspection.

Case Study- Vial Haze Situation became:

FDA, CMO and Commercial client all agree a study of haze is needed prior to lot release.

One clinical client passionately wants to argue against any hold; insists on teleconference negotiation, based on empirical data (safety level of ammonium sulfate, widespread use of ammonium sulfate, etc.).

Case Study- Vial Haze Resolution: study of vials revealed that post-washing haze

is residual moisture, and disappears after drying. SOPs revised to provide directions for treated vials.

Analysis: different clients can have vastly different priorities, different approaches to working with FDA. CMO needs to be flexible, but cannot jeopardize patient safety, and should maintain positive status with agency regardless of client directives.

Action: Include clear direction in Quality Agreement regarding agency agreements and commitments

Case Study- Holy Vials One vial is observed to be leaking out of the side of the

vial.

Vial manufacturer claims it is unrelated to them, “millions of vials with no such events”; must have been caused at CMO

No other leaking vials seen in multiple lots over 6 month period, media fills all pass,

As Deviation is about to be closed, two more leaking vials are discovered.

Case Study- Holy Vials All three leaking vials are from same mold number; no

definitive root cause

Client insists on culling the defect on existing inventory; CMO agrees, but also insists on client notifying agency. Client disagrees.

Client concerned with compliance/safety versus lost revenue; CMO concerned with compliance/safety only

Client eventually explains the full nature of the defect

Recall decision is made

Holy Vials- lessons learned Analysis: CMO discovers an issue which CMO believes

requires a notice to office of Product recall. Client disagrees.

CMO will be held accountable during inspection; client

insists they will have someone there to explain the situation to inspector- not a good option

Client has their product success as the top priority; CMO has all products as the top priority

CMO cannot allow one product (client) to put all other products at risk

Holy Vials- lessons learned

Resolution: Agency eventually informed, recall made, defective vials culled

Vial manufacturer admits to defect, replaces molds

Action: Provide clear directives in QAG regarding right of CMO to notify agency of potential safety issues

Holy Vials- lessons learned CMO strongly recommends moving away from that

vendor, due to numerous other quality issues associated with large (50, 100 ml) molded glass vials. CMO quality system must continue to monitor, without effective CAPA’s, quality of incoming vials

Client refuses to change vials, claims regulatory hurdles are preventative (E/L, CCIT, machinability, water and media fills, etc..)

Looking Ahead What can be improved?

Communications

More frequent, more open

QAG Details

Expectations

Understand each other’s role

Agree on Quality Standards

Agree on Final Decision-makers: CMO

vs Client