It is Never Too Late to Document Your Cold Chain Process Validation Approach

Documentation strategy for your cold chain management validation practices has evolved over the last several years. The FDA and other regulatory agencies are requesting more and more specific information in the filing to confirm the impact to drug product during transport, and the effect transportation hazards have on shelf life. An overall strategy of providing minimal documentation in the Biologic License Application (BLA) has evolved to provide a more complete and comprehensive review of the stability data, verification studies, packaging qualification and process validation activities in the BLA to support questions in the pre-approval inspection (PAI). The outdated “don’t ask, don’t tell” approach has given way to provide cold chain qualification and validation data that is reviewable by regulators and is expected to be discussed in the PAI process. More and more, data that has not been submitted and reviewed in the BLA is more difficult to use as justification for temperature ranges set outside of labelled storage conditions or justification for drug product release after excursions in distribution outside of labelled storage conditions.

Documentation for sections 3.2.P.3.5 Process Validation as it pertains to distribution and cold chain activities should include the following elements:

Packaging Qualification

Primary packaging – container closure integrity, sterile barrier, physical integrity, and leachables and extractables after agitation Secondary packaging – physical integrity and label legibility Thermal packaging – physical integrity and thermal control (after physical integrity testing) Process Validation

Performance qualification in qualified packaging in representative transport lanes Drug product physical stability studies with release testing Documentation for sections 3.2.P.8.3 Stability Data as it pertains to distribution and cold chain activities should include the following elements:

• Long-term stability studies per ICH Q1A Stability Testing of New Drug Substances and Products for confirmation of shelf life

• Accelerated stability studies per ICH Q1A Stability Testing of New Drug Substances and Products for justification of effects of temperature exposure outside recommended storage conditions

• Additional temperature-stress studies to evaluate the effect of short-term excursions of temperature outside recommended label conditions per ICH Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological / Biological Products

The BLA submission is the opportunity to show the qualification and validation data and support stability studies. The PAI inspection process is the opportunity to show process controls. The focus at the PAI is to review the validation master plan documentation to show the proper process controls are in place to confirm the product quality limits demonstrated in the BLA are achievable. The focus in the PAI should be in two key areas:

Standard Operating Procedures

Product put-away and storage Inventory control Drug product picking Pack-out instructions for thermal packaging Nonconformance Management

Monitoring and controls Allowable exposure limits outside of labelled storage conditions with supporting stability studies Material traceability / inventory control processes A medicinal product can take a variety of paths from the manufacturer to the patient. In some instances, a drug product can route directly to the patient. In others, there are a series of lanes in the distribution chain where the drug product may be subject to variable environments. Principles of process validation (including design, operational and performance qualifications) can be applied with good distribution practices (GDPs) to confirm portions of the supply chain are validated (excluding unforeseen transport events and the impact of extreme weather conditions).

An Implementation Strategy is Key

Your implementation strategy for preparing for BLA submission and the subsequent PAI should be well- defined and understood by all key stakeholders in the cold chain as quickly as possible. Your approach should be documented in a validation master plan. Some keys to success to consider are:

Network Design and Partner Selection:

1. Confirm expected channels of distribution as soon as possible

2. Select channel partners and physical location(s) for each channel of distribution

3. Conduct site assessment and quality management systems review

4. Prepare assessment report and track improvement against recommendations

5. Execute quality agreement as part of commercial terms

6. Implement management review metrics as part of management review process

Packaging Qualification :

1. Clearly define your temperature profiles and your justification for use

2. Perform operational qualification (OQ) study designed to expose the drug product to an approved composite (or representative) simulation of the distribution environment

3. Confirm or conduct operational and performance qualification (PQ) on the shipping systems as required (active vs. passive) after vendor data evaluation

4. Design monitoring and controls strategy based on qualification data

Process Validation and Shipping Studies:

1. Create validation master plan for drug product validation activities

2. Examine the interaction of each primary container type with the product for possible interactions.

3. Generate physical stability at the earliest possible opportunity in development with bulk secondary packaging

4. Apply to all subsequent secondary packaging since hazard exposure will exceed any within the commercial supply chain

A validation master plan for distribution along with specific product annexes can align the disparate activities already completed into a comprehensive and cohesive approach to distribution process validation. The validation master plan gives an opportunity to discuss risks and mitigation strategies , qualification approach, validation approach, and monitors and controls. Sections can include discussion on warehousing and storage, product transportation, shipping configurations, methods of temperature control, and packaging.

Shipping studies must include both physical packaging integrity and drug product quality. Any proposed shipping qualification plan that does not include any testing of drug quality post shipping compared to specifications and/or control samples will be challenged. The regulatory agencies are expecting to see some post-shipment drug product studies to confirm quality after transport.

Protocols for shipping studies should be split into operational qualification (OQ) and performance qualification (PQ) - each type of protocol achieves difference results. The OQ protocols show in controlled laboratory conditions that the control in the proposed design space is achievable. The PQ protocols show in field conditions the process is robust and repeatable.