Shipping Validation Strategies for SMEs

Property of BioVectra Inc.

© 2015

BioVectra Profile

• Founded in 2001; origins 1970

• Privately held until 2013

• Now part of Mallinckrodt Pharmaceuticals

• 260 employees

• BioVectra is focused on Pharmaceutical and Biotechnology

Charlottetown Facilities

Windsor Facility

Our Services

• cGMP custom API synthesis

• cGMP Fermentation

• Bioextractions & purifications

• Bioconjugation and MPEG reagents

• Partnered drug development programs

• Specialty biochemicals & enzymes

“Experience Versatility”

cGMP API Manufacturing

• 4 FDA inspected manufacturing facilities

• 110,700 sq. ft. of manufacturing space

• Diverse project scope: research, clinical, commercial

• History of cGMP manufacturing and documentation

Case Study #1 – Eastern Europe

Conditions:

1. Temperature control range +2 to +8°C with allowable excursions down to -20°C and up to +25°C

2. Budget considerations

3. Prequalified active or passive shipping container

4. Shipping solution must be validated

BioVectra needed to

ship formulated bulk

drug product from

PEI Canada to

Eastern Europe

Validation Strategy

Include program partner(s)

Conduct risk assessment

• Defines framework for identifying shipping container solution and service providers

Establish regulatory compliance requirements

• Do this as early as possible

Engage validation project partners

Define responsibilities and develop validation protocol

• Thermal qualification verification phase only

Execute the protocol, compile results and write final report

Risk Assessment

• Stability study

• Control options

• Passive versus active?

Temperature requirements

• Origin and destination known. What lies in between?

• Available service options?

• Are there finite time constraints?

Routing and Time

Product packaging

Cost

Security

Regulatory Considerations

Customs and OGD/OGA requirements

Export Screening

• Denied party/entity screening

• Area Control List considerations

• Sanctions

Licenses and Permits

• Export/import

• Controlled Substances

• Chain of Custody

Prior notifications and/or registrations

• Human or animal health agency requirements

• Origin health certification

• Environmental regulation

Roles and Responsibilities

BioVectra

• Defining the temperature control range

• Identifying suitable pre-qualified pack-out system and logistics partners

• Preparing, reviewing and approving the shipping validation protocol and report

Logistics services provider

• Defining the routing and identifying suitable sub-contract carriage partners (where applicable).

• Managing the shipment from pick-up through to delivery.

• Addressing any transport deficiencies to ensure the final report package can be approved by BioVectra.

Roles and Responsibilities

Shipping container solution provider

• Providing pre-qualified shippers, and all associated assembly/use instructions.

• Providing technical expertise and advice, as required.

CMO/Recipient

• Receiving the shipment(s) and supporting the validation as prescribed.

Our Validation Partners

Softbox Systems Inc.

• Medium Pallet Shipper

Sensitech Inc.

• TempTale®4

DHL Global Forwarding

• Logistics Services

Medium Pallet Shipper

Passive design

• 120 hour control High performance

• Performance Validation Protocol & Report Qualified

• SOPs provided Easy assembly & use

• Willing to work with clients to solve unique technical challenges

Strong technical support

Softbox Systems Inc.

Sensitech Inc.

TempTale®4

• Single or multi-use

• Acceptable accuracy and resolution

• Data sampling interval 10 sec up to two hours

• 16,000 data points

• One year battery life

• Alarm functions, delayed start, FAA compliant

International Certificate of Validation

• Valid for one year

DHL Global Forwarding

• Pharma industry understanding

• Underlying support systems

• Existing relationship with consignee

Strong presence and expertise shipping

into Eastern Europe

Able to establish routing plan, develop routing SOP, conduct

training

• Intervene if necessary

• Facilitate import clearance Manage shipment throughout journey

Planned Routing

• Controlled temperature truck (+15 to +25°C)

Depart Charlottetown (Day 0)

• Stored in DHL warehouse; ambient warehouse temperature

Arrive Montreal (Day 1 – 24 hours)

• Transferred using temperature controlled truck and stored in appropriate holding area to await aircraft loading

Transfer to Montreal Airport (Day 2 – 36

hours)

• Exposed to outside ambient temperature during aircraft loading

Depart Montreal (Day 2 – 48 hours)

Planned Routing

• Exposed to outside ambient temperature during aircraft offloading

• Stored in appropriate holding area at airport o/n

Arrive Munich (Day 3 – 60 hours)

• Departure by ground to Vienna using regular or thermo truck, depending on availability

Depart Munich (Day 4 – 84 hours)

• Stored in appropriate holding area until recovery of goods by DHL using temperature controlled truck (+2 to +8°C)

Arrive in Vienna airport (Day 5 – 108 hours)

Transport to destination facility (Day 6/7 – 132/156 hours)

Validation Experience

• Controlled temperature truck (+15 to +25°C)

Departed Charlottetown

(Day 0 – Dec 11)

• Stored in DHL warehouse; ambient warehouse temperature

Arrived in Montreal (Day 1

– Dec 12; 24 hours)

• Transferred using temperature controlled truck and stored in appropriate holding area to await aircraft loading

• Shipment was “bumped” by airline

Transferred to Montreal Airport (Day 2 – Dec 13; 48 hours)

Depart Montreal (Day 4 – Dec 15;

96 hours)

Validation Experience

• Exposed to outside ambient temperature during aircraft offloading

Arrive Munich (Day 5 – Dec 16; 108

hours)

• Departure by ground to Vienna using ambient temperature truck; scheduled thermos truck not available due to previous delay

Depart Munich (Day 5 – Dec 16;

112 hours)

• Stored in appropriate holding area until recovery of goods by DHL on Dec 18 using temperature controlled truck (+2 to +8°C)

Arrive in Vienna airport (Day 6 –

Dec 17; 136 hours)

Transport to destination facility

(Day 7/8 – Dec 19; 184 hours)

Incidents and Investigations

DHL reported the following incidents:

The shipment was “bumped” Dec 13 in Montreal by the airline. This incident had no direct impact on the TQV outcome. The change did however affect pre-scheduled routing out of Munich as described below.

The transport from Munich to Vienna by road did not happen using a Thermo truck as originally scheduled for Dec 15 because shipment scheduled for departure Dec 13 out of Montreal was “bumped” by the airline. The change caused the Thermo truck to be unavailable Dec 16. DHL then used the first available truck to transport the goods to its Austrian location to minimize risk. No problems were noted or encountered as a result of this change.

Incidents and Investigations

BioVectra’s development partner noted the following:

The initial payload temperature dropped below 2°C for approximately 10 hours, but did not fall below 1°C. After discussing the observation with Softbox engineers, it was concluded that this observation was likely caused by insufficient thermal mass at minimum load. Since the temperature was never outside the allowable and defined excursion range, no corrective action has been deemed necessary.

Validation Results

Shipper #

Temperature Recording

Device Serial Number

Acceptance Criteria Requirements

Acceptance Criteria Met (Yes/No)? +2° to +8°C for a

minimum of 120 Hours (Yes/No)?

Total Duration (Hours)

Structural Integrity Maintained (Yes/No)?

1 2938302799 Yes 183.9 Yes Yes

2938302820 Yes 183.9 Yes Yes

2 2938302794 Yes 184.2 Yes Yes

2938302800 Yes 184.2 Yes Yes

3 2938302801 Yes 183.5 Yes Yes

2938302821 Yes 183.5 Yes Yes

Case Study #2 – India

Conditions:

1. Temperature control range +2 to +8°C with allowable excursions down to +1°C and up to +25°C

2. Passive or active shipping container required

3. Zero breakage

4. Shipping solution must be validated

BioVectra needed to

ship formulated bulk

drug product from

PEI Canada to India

Choosing the Right Partner

BioVectra had limited experience

• We needed help

Conducted research

• Investigated trade publications/online resources

• Talked with our drug development partner

• Talked with our existing logistics services providers

Evaluated potential service providers

• Considered their experience

• Previous shipping validation projects

• Assessed their recommendations for specific routing, shipping container options, and validation program support

LifeConEx

• Formerly a 50/50 joint venture with Lufthansa Cargo

• Continued autonomy to work with carriers and service providers outside DHL, where mutual benefit exists

Wholly owned subsidiary of DHL Global Forwarding

• It’s all they do; no distractions or competing interests

• Can manage the whole process; extensive network with global reach

Temperature management specialists

Invest in technology

GDP understanding and know-how

LifeConEx Process

Analyze

Optimize

Manage

Review

Routing Analysis

Access India via Europe

• Best air cargo routing options

• YYG, YUL, LHR, HYD

Mumbai or Hyderabad?

• Mumbai congested

• Not enough cold chain infrastructure

• Custom clearance delays expected

• HYD infrastructure investment in cold chain facilities

• Less congested; modern highway to destination

• Further away

Additional import requirements

• Import permit required for goods; engage consignee

• How to manage payment of duties and taxes?

Why a Custom Solution?

Routing constraints

• Slow and unpredictable customs clearance

• Especially through Mumbai

• Active pack out options not authorized for inland delivery; temperature excursion risk associated with product transfer at airport considered too high

• Limited pharma product controlled temperature shipping/storage infrastructure in destination country; extended time passive control solution indicated

• High risk of exposure to extreme temperatures

No existing qualified solution available in context of above constraints

Shipping Solution Validation

Define project scope and assign responsibilities

• Leverage development partner and service provider expertise and resources

Review routing, risks, compliance requirements

Identify qualified test facility, or facilities

• Use an existing shipping container design adapted to BioVectra application

• One facility may not be able to support all needs; sub-contract where it makes sense

• Collaborate with your development or service providers to help identify the best firms to work with

Roles and Responsibilities

BioVectra Defining the temperature control range

+2 to +8°C with allowable excursions down to +1°C and up to +25°C

Identifying extreme temperature “spike” conditions to be incorporated into the solution design

Two (2) x eight (8) hour -20°C spikes were included in the cold profile, and one (1) eight (8) hour +40°C spike was included in the heat profile

Providing glass bottles, caps, and tamper evident seals used to package simulated product during testing

Reviewing and approving all protocols and reports

Preparing and approving a final summary validation report

Roles and Responsibilities

• Establishing routing SOP

• Identifying an appropriately qualified test facility

• Managing the project through to completion

• Addressing deficiencies to ensure the final report package can be approved by BioVectra

• Managing the logistics during TQV, or as required in support of project activities

LifeConEx

Roles and Responsibilities

Test Facility Firm #1

• Conducting Proof of Concept, TDQ, TOQ, and TQV testing

• Writing, editing and approving necessary protocols and reports

• Providing technical expertise and advice

• Providing shippers, gel packs and pack out instructions

• Managing Physical Qualification and Vibration Testing at Test Facility Firm #2

Test Facility Firm #2

• Conducting Physical Qualification and Vibration Testing according to requirements defined by Test Facility Firm #1

• Preparing the corresponding technical reports

Validation Process

Step 1

• Proof of Concept

• Used to establish foundation for TDQ

Step 2

• Thermal Design Qualification (TDQ)

• Based on International Safe Transit Association (ISTA) 7E Heat and Cold profiles (ISTA 7E 2010. Version date: October 2010 initial release); Temperature spikes introduced into ISTA standard profile

Step 3

• Thermal Operation Qualification (TOQ)

• Conducted to prove the ability of the shipper to repeatedly maintain simulated product within defined temperature range

Step 4

• Physical Qualification (PQ)

• Conducted to assure the impact of handling the shipper throughout the distribution cycle does not jeopardize the shipper’s structural integrity

Step 5

• Vibration Testing

• Performed on the bulk formulated drug product bottle and closure system to provide assurance closure integrity is maintained during transport

Step 6

• Thermal Qualification Verification (TQV)

• Conducted to prove the ability of the shipper to repeatedly maintain simulated product within defined range following prescribed routing SOP

Validation Results

Shipper #

Temperature Recording

Device Serial Number

Acceptance Criteria Requirements

Acceptance Criteria Met (Yes/No)? 1°C – 25°C for a

minimum of 144 Hours (Yes/No)?

Total Duration (Hours)

Structural Integrity Maintained (Yes/No)?

1 3480142331 Yes 229 Yes Yes

3480142398 Yes 229 Yes Yes

2 3480142393 Yes 230 Yes Yes

3480142396 Yes 230 Yes Yes

3 3480142360 Yes 231 Yes Yes

3480142367 Yes 231 Yes Yes

Contact Information

www.biovectra.com info@biovectra.com

BioVectra Inc.

11 Aviation Avenue

Charlottetown, PE

C1E 0A1

Tel: (902) 566-9116

Toll Free: (866) 883-2872

Fax: (902) 628-2045