Slide 1 © PharmOut 2018

Sponsor – Contract Manufacturer Relationship in Clinical Supplies

Presented by Yaara Dromi,

August 2018

Slide 2 © PharmOut 2018

Sponsor – Contract Manufacturer Relationship

Sponsor/Contract Giver Responsibilities

Sponsor/Contract Giver Requirements

Contract Acceptor Requirements

Challenges of Clinical Supplies

How to Execute the Ultimate Responsibility by Sponsor/Contract Giver?

Slide 3 © PharmOut 2018

Guidelines

Please contribute

Please stop me to ask a question

Please relax and enjoy yourself

Please place your phone on silent mode

Slide 4 © PharmOut 2018

Sponsor Responsibility (Clinical Supplies)

• PE009-13, the PIC/S, Annex 13, Manufacture Of Investigational

Medicinal Products

Co-operation is required with trial sponsors who undertake the ultimate

responsibility for all aspects of the clinical trial including the quality of

investigational medicinal products.

Slide 5 © PharmOut 2018

Contract Giver/Owner Responsibility (Commercial)

• PE009-13, the PIC/S guide to GMP for medicinal products, Chapter 7:

Outsourced Activities

“The Contract Giver is ultimately responsible to ensure processes are in place to assure

the control of outsourced activities.“

• FDA – Contract Manufacturing Arrangements for Drugs: Quality Agreements

Guidance for Industry

“When an owner uses a contract facility, the owner’s quality unit is legally responsible for

approving or rejecting drug products manufactured by the contract facility, including for

final release.”

Slide 6 © PharmOut 2018

Contract Giver/Owner Responsibility (Commercial)

• ICH guidance for industry Q10 Pharmaceutical Quality System

The pharmaceutical company is ultimately responsible to ensure processes are in place to

assure the control of outsourced activities and quality of purchased materials.”

Slide 7 © PharmOut 2018

Contract Giver (PIC/S, Chapter 7)

• Assessing the legality, suitability and the competence of the Contract Acceptor to

carry out successfully the outsourced activities.

• The Contract Giver is also responsible for ensuring by means of the contract that

the principles and guidelines of GMP

• Provide the Contract Acceptor with all the information and knowledge necessary

to carry out the contracted operations correctly in accordance with regulations in

force, and the Marketing Authorisation for the product concerned.

Slide 8 © PharmOut 2018

Contract Giver (PIC/S, Chapter 7)

• Monitor and review the performance of the Contract Acceptor and the

identification and implementation of any needed improvement.

• Responsible for reviewing and assessing the records and the results related to

the outsourced activities.

• Ensure that all products and materials delivered to him/her by the Contract

Acceptor have been processed in accordance with GMP and the Marketing

Authorisation.

Slide 9 © PharmOut 2018

Contract Acceptor Requirements

• Must have adequate resources to perform the work ordered (premises,

equipment, knowledge, personnel)

• Ensure suitability of products, materials and information received

• Should not subcontract without formal approval by Contract Giver

• Should not make unauthorised changes that may adversely affect the outsourced

activity.

• Should understand that the activities may be subject to audit

Slide 10 © PharmOut 2018

Challenges in Clinical Supplies

Data Integrity

Blinding of packaging material

Blinding investigational product Vs. Comparator/

Placebo

Maintaining randomisation

Products/ processes are in different

development stages

Slide 11 © PharmOut 2018

Imagine….

Yaara50 (A) Placebo to match Yaara50 (P)

Pharmout100 (A)A, A A, P

Placebo to match Pharmout100 (P)P, A P, P

1. Product Yaara50 is a 50mg tablet to be tested in comparison to comparator/ placebo

2. Product Yaara50 is a 50mg tablet to be tested for dose and therefore we will need the following doses:• 0mg• 50mg• 100mg• 150mg

3. Product Yaara50 is a 50mg tablet to be tested in combination with Pharmout100 (100mg) for the interaction. What are the options of combinations including placebo to both products?

Slide 12 © PharmOut 2018

Imagine

4. Combination of 2 pathways to achieve the requested effect.

• Pathway A: Product A1, A2 (Comparator to A1), PlaceboA

• Pathway B: Product B1, B2 (Comparator to B1), PlaceboB

A1 A2 PlaceboA

B1 A1, B1 A2, B1 PlaceboA ,B1

B2 A1, B2 A2, B2 PlaceboA, B2

PlaceboB A1, PlaceboB A2, PlaceboB PlaceboA, PlaceboB

Slide 13 © PharmOut 2018

How to Execute the Ultimate Responsibility?

Evaluate

Contract

Information Transfer

Controls

Communication

Continuous Review

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Evaluate the Contract Acceptor

Evaluation is performed in a few steps:

1. Questionnaire

2. Certificates (GMP, ISO, Lab testing)

3. Audit

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Audit

• When auditing a potential contract manufacturer ask the hard questions

• Examine the performance of the quality system

• Look at registers! (an empty register should raise an alarm)

• Basic GMP requirements: Line clearance, reconciliation, product segregation and

disposition, cleaning, MBR generation

Finally

It is OK to identify that a potential contractor is not suitable to be

contracted and continue to search for a more suitable one.

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Contract

• Determined the standard to follow

• Identify who is responsible for each activities

Activity Contract Giver Contract Acceptor

Write MBR X V

Approves MBR V V

Review executed BR V V

Release batches V X

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Information Transfer

• Transfer all applicable information/knowledge to contract acceptor to allow the

contractor to plan prepare, implement changes and controls for the purpose of

execution of the contract

Contract acceptor

Product information

Study protocol and design

Process requirements

Quantities Time lines

Distribution

Randomisation

Contact details

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Controls

• Testing of product

• Sampling method

• Review final product before release (physical product or photographic evidence)

• Review of Batch Records

• Designed release process

• Control of distribution

Strategy for all the above should be risked based and on the basis of experience

with the contractor and build of trust. This will be specified in the contract.

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Communication

• Continuous communication and report of issues in real time

• Communication must go both ways

• Communication must be clear and unambiguous

• Information should be delivered in appropriate time frame to allow parties to

respond:

• Due dates and required quantities

• Issues raised during processing

• Changes in processes/expectations/timelines

Slide 20 © PharmOut 2018

Continuous Review

• Review of performance and KPIs

• General discussion and planning

• Continuous improvement activity and monitoring

The review allows the Sponsor/Contract Giver to evaluate the performance of

contractors and continue to select the best performing contractors.

Sponsor may chose to reduce/stop engagement with unsatisfactory contractors or

enhance work volume with best performing contractors.

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Recap?

Clinical supplies are more complicated and therefore susceptible to error than commercial.

Sponsors holds the ultimate responsibility to the patients safety and trial integrity.

Sponsors must apply control strategy to assure their responsibility

Slide 22 © PharmOut 2018

Keep safe and manage ethical trials!

Yaara Dromi

Yaara.dromi@pharmout.net

Consultant