Cost of GMP in Nuclear Medicine(Cold Kit)

Sanjay K Sharma MSc, PhD, PChem

Director, Scientific and Operations

Edmonton Radiopharmaceutical Centre

Edmonton-Alberta

2

What is ERC

Edmonton Radiopharmaceutical Centre-AHS

• Products

Cold Kits- MDP-10, MDP-21, DISIDA, DTPA,

MAA, SC, AS, Pyro

Iodine- 131I-Ther (Inj.), Oral131I-Diag (Inj.), Oral131I-mIBG (Diag.), 123I-mIBG

SPECT 13 Products

PET FDG

Clinical trial 177Lu-DOTA-TATE, Na18F

Clients 30 (AB and in Canada)

3

Introductory Statements and Considerations

• All conclusions are derived from economical considerations,

not technical

• Very good science is not sufficient to bring a drug on the market

• Radiopharmaceutical industry (RPI) is now fully mature but does

not have the funds to fully develop RPs

• Today Conventional Pharma Industry (CPI) is not (yet) interested

in RPs (and absolutely not in diagnostics)

• Regulatory constraints will not be weaker in the future

• Awareness about potential and successes of radiopharmaceuticals is

very weak

4

Health Care-CANADA

• Canadians are very attached and proud of their health care

system (Quality)

• Canadians are very supportive of the principles of the

Canada Health Act

• But this Quality of Health Care is associated with a COST to

the providers

• This Cost is effecting the field of Medicine too

• In Nuclear Medicine, as in other medical fields, we are

under increasing pressure to lower costs and to gain the

most benefit from the dollars we spend.

5

Not here to argue with any Regulators

But…

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Radiopharmaceuticals

• Hold promise for diagnosing disease

• Monitoring disease progression

• Tracking therapeutic response

• Knowledge of physiology and pathophysiology

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Radiopharmaceuticals

• Radionuclide Itself 99mTc Pert, Na18F

• Pendant/Molecular Scaffold 99mTc-MDP, 99mTc-DISIDA, 99mTc MIBI etc68Ga-DOTA/TATE/TOC, 18FAlkF

• Tracer Incorporated Estradiol, 11C, 13N, 15O

8

Challenges for Radiopharmaceuticals

• Comparison with therapeutic agents

Same path of development as therapeutic agents

• Target Validation

• Lead candidate identification

• High Affinity

Target/Non-Target distribution

• Adequate clearance

• Low Toxicity

• Multiple phase clinical trials

• Similar Regulatory submissions

9

Drug Development

10

Economics of Diagnostic Agents

• Market of therapeutic drugs world wide is close to $962.1

billion

• Market of Diagnostic agents worldwide is $3.8 billion

• Pfizer alone is $6.5 billion

Small/Specaility category of therapeutic drugs

Handful of players involved in Diagnostic agents

development

11

How we are Surviving

• Academia

• Active and Research academic

investigators

• Funds/Grants are drying

• Administrative hurdles

• Strict regulatory guidelines

• Industries

• Small to medium sized industries

• Low revenue

• Strict Regulatory requirements

12

What Happened ?

• Regulations of Therapeutics drugs implemented on

Diagnostic Agents

• All the developments and clinical productions of

Diagnostic agents still in Academia or in Hospitals

Huge infrastructure investment (retrofitting)

Quality Assurance Department

13

Where we stand today

14

an Analogy

15

What is GMP

Good Manufacturing Practice (GMP) is a concept in

pharmaceutical regulation which aims to ensure

consistent production of a safe and effective product.

The three main components are

• Facilities

• Documentation

• Training.

16

Importance of GMP

• 1937 Elixir Sulfanilamide (diethyl glycol as a solvent)

– 100 deaths

• 1960 Thalidomide Tragedy

– Birth defects

• 2012 New England Compounding Center

– 48 died fungal meningitis infections

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Importance of GMP

• GMP is based on good science

– GMP ≠ generate more paper

• One of the pillars of science is that you can prove it.

– We’re in the “prove it” business.

• We need to ensure that the GMPs for

radiopharmaceuticals don’t stray from this concept.

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There is a Cost to Quality/Compliance

• I do think that additional work is needed to help

Centralized Radiopharmacies get the best bang for their

quality dollar.

• Industry and Health Canada are ultimately on the same

side and have the same goal.

– High quality product

– Ensure patient safety

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Elements of GMP

• Facility Design to control operations

• Adequate documentations/records

• Production and process controls

• Quality Assurance/Quality Control

• Validations

• Equipment's Qualification

• Environment Monitoring

• Personnel Training and Certification

• Environment Monitoring

• Equipment Validation

• Processes Validation

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Environmental Monitoring

• Environmental monitoring describes the processes and

activities that need to take place to characterize and monitor

the quality of environment

• Environmental Monitoring is a surveillance system for

microbiological control of cleanrooms and p\other controlled

environments. It is a process which provides monitoring,

testing and feedback to the biological quality levels in

aseptic environments.

21

Monitoring Frequencies

• Daily Monitoring LAF/Passbox/Manufacturing Room/

Hallways

• Monthly Monitoring Manufacturing area/Equipments

• Quarterly Monitoring All the above plus Compressed air

• Half Yearly Monitoring Operators (Media Fills)/Personnel Yearly

HVAC/AHU/BAS system validation

• Occasional Monitoring As and when required

22

HVAC Monitoring

Monitored yearly

Parameters

– Temperature/RH

– Air Velocity

– Air Change

– Filter Integrity

– Non-viable air borne particles

– Vialble Air Borne particles

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Validation

• Validation is establishing documented evidence which

provides a high degree of assurance that a specific

process or equipment will consistently produce a

product or result meeting its predetermined specification

and quality attributes

• Confirmation by examination and provisions of objective

evidence that the specified requirement have been

fulfilled

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Phases of ValidationDesign Qualification (DQ)

Documented verification of the design of equipment and

manufacturing facility

Installation Qualification (IQ)

Documented verification that the equipment is installed as

designed

Operational Qualification (OQ)

Documented verification of equipment or system

performance in the target operating range

Process/Performance Qualification (PQ)

Documented verification that the equipment or system

operates as expected

25

Key validation documents

• Validation Master Plan (VMP)

• User Requirements

• Functional Specifications

• Validation Protocols

• Standard Operating Procedures (SOPs)

• Validation Final Reports

• Change Control System

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Validation contd.

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Equipment Qualification and Cost

• Design, Requirement, Purchasing

• Regulatory requirements for Validation

Establishing documented evidence, which provides a

high degree of assurance that a specific process will

consistently produce a product meeting its pre-

determined specifications and quality characteristics

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Design-Validation Relationship

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Re-Qualification

Event Driven

• Replacement of critical Components

• Change in process or procedure

• Change in personnel

• Failure Investigation

Time Driven

• Change of “the little things” over time

• Poorly maintained system

• Routine system failure

• Environment dependent

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Success and Difficulties in Validation

Success

• Getting Validation personnel involved early in the process

• Well defined user requirements and specifications

• Integrating Validation into design-build-test-use cycle

• Good Communication

Difficulties

• Inadequate definition of system requirements/specifications

• Poor Protocols

• Inadequate resolution/explanation of failures/deviations

• Poor planning

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Summary of Validation

• As the User, know your requirements and processes

• Validation is a lifecycle approach. Its not a one time and

done

• Be cognizant of change control

• Understand the functionality of the units being qualified

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Equipment Validation-Vial Filler• Customized Unit

• Semi Automatic Unit

• Filling under Class A

• Nitrogen Purging

• Half Stopper

• Pressure Crimping

• Semi Reject Station

• Star Wheel for 10,

20, 2 mL vials

• Different Volume

dispensing

• $169,000.00

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Cost of –OQ and PQ on Vial Filler

Size of

Vial

# Vials # Runs Total

Vials

$/vial Total

Cost

20 mL 750 2 1500 5.40 8,100.00

10 mL 1100 2 2200 5.40 11,880.0

2 mL 2500 2 5000 3.50 17,500.0

Filling Precision Study-50% of the Batch Size

Total = $ 37480.00

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Cost of –OQ and PQ on Vial Filler

Production Stimulation-50% of the Batch Size

Size of

Vial

# Vials # Runs Total

Vials

$/vial Total

Cost

20 mL 750 1 750 5.4 4050

10 mL 1100 1 1100 5.4 5940

2 mL 2500 1 2500 3.5 8750

Septum 4350 1 4350 0.58 2523

Crimp 4350 1 4350 0.08 348

Total = $ 21611.00

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Cost of –OQ and PQ on Vial Filler

Performance Qualification Full Batch Size

Size of

Vial

# Vials # Runs Total

Vials

$/vial Total

Cost

20 mL 1456 1 1456 5.4 7862.0

10 mL 2200 1 2200 5.4 11361.0

2 mL 5000 1 5000 3.5 17500.0

Septum 8510 1 8510 0.58 4935.0

Crimp 8510 1 8510 0.08 680.0

Total = $ 42,340.00

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Processes Validation

• Product using 20 mL vial

• Three runs

Cost for process

• Material cost $12948.00/run

• Material cost for three runs $38844.00

• Time A minimum of 10 working days

• Staff A minimum of two staff (not including QA,

Scientific)

• A total of $47,000.00/Processes validation of this

product* The API required for this product is manufactured by ERC

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Processes Validation

• Product using 10 mL vial

• Three runs

Cost for process

• Material cost $18393.00/run

• Material cost for three runs $55179.00

• Time A minimum of 10 working days

• Staff A minimum of two staff (not including QA,

Scientific)

• A total of $65000.00/Processes validation of this

product

* The API required for this product is manufactured

by ERC

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Processes Validation Cost

Product Cost

20 ml Vial (two Products) $94,000.00

10 ml Vial (six Product) $390,000.00

Total $484,000.00

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Validation of a Lyophilizer

• Lyophilization is a process in which water is removed from

a product after it is frozen and placed under a vacuum,

allowing the ice to change directly from solid to vapor

without passing through a liquid phase

• The process consists of three separate unique and

interdependent processes, freezing, primary drying

(sublimation) and secondary drying (desorption)

40

Validation

• Establishing a commercial lyophilization process can be

very challenging

• Successful validation requires robust development studies,

equipment qualification and process validation.

• Not enough focus on developing the freezing phase which

is the most important phase of the cycle.

• Continued Processes Validation (CPV): Ongoing

assurance is gained during routine production that the

process remains in a state of control

41

Lyophilizer Qualification

Equipment Qualification

• Temperature mapping

• Leak test

• Condenser capacity

Processes Qualification

• Depending on the number

of products

• Stability of the products

• Excipient

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Cleaning (CIP) and Sterilization

• Perform between each run

• Clean-in-place(CIP) manual or automatic

- CIP cycle-initial rinse, recirculation, final rinse, drying

- CIP-CV should demonstrate total chamber coverage

(riboflavin)

• WFI is preferred

- Cleaning agent validation is required

- Cleaning processes needs validation

• Sterilization

- Should be sterilized after CIP, Typically Steam sterilization

- Sterilization-Validation

- Heat distribution and biological indicators

- Unit should be dry after sterilization

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Cost of PQ on Lyophilizer

• Three type of vials

• Two runs

50% Load

750 x 2 x 5.40 = $8100.00

1100 x 2 x 5.40 = $11,880.00

2500 x 2 x 3.40 = $17,000.00

100% Load

1500 x 2 x 5.40 = $16,200.00

2200 x 2 x 5.40 = $23,760.00

5000 x 2 x 3.40 = $34,000.00

Total = 110,940.00

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Processes Validation-Lyophilizer

• Number of product

• API cost

• Number of runs

• Pre-release Specifications

• Sampling size

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Product Validation

• Product (1, 2200 vials), API (ERC), Runs (3), Specification

test (10), Sample size (250 vials)

• API (416 x 3) $ 1250.00

• Vials (2200 x 3 x 5.4) $35640.00

• Specifications (10 x 3)

• Internal Test - Visual, Leak Test, Labelling/24h Stability,

Tin Assay, Endotoxin

• External Test - N2/O2 content, Chemical content,

Sterility, Biological Distribution/Functional Imaging

$260340.00

Total = 297320.00

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?

Total cost of validation of this one product

• Vial Filler IQ +OQ + PQ + PV =$166461.0

• Lyo IQ + OQ +PQ + PV =$309200.0

$475661.0

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Questions?

Is it necessary to do all this?

Can we afford all this cost?

Should we stop making these products?

Is there any solution?

YES

NO

NO

???????

48

?

How to persuade someone to begin developing a new agent

• To make a sale of $1-2 million to recover the cost

• An example of a Kit which only ERC produces

Total sale should be ~ 28571 vials/year

Estimated Revenue $1,000,000.0

our total production is ~8400 vial/year

Revenue of ~$300,000.00

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Options

• Decrease the cost of bringing a drug to the market

• Charge more for a unit of drug

• Increase use of drug

51

Suggestions

• More discussions within CARS-CANM-BGTD

• Increase relationship/partnership between Industries and

Academia

• Harmonized Market Authorization

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Thank you for listening