Tech Transfer Risk

Lessons Learned, Next Steps
Alkermes has found the framework described here very valuable in executing efficient tech transfers and has received favorable feedback from their partners on its use. The framework is now integrated with, and flows into, the three-stage risk assessment process that forms part of the implementation of the new Process Validation Guidance issued by the FDA in January 2011 – Stage 1, Process Development risk assessment, Stage 2, Process Performance Qualification (PPQ) risk assessment and Stage 3, Continuous Process Verification (CPV) risk assessment. This process is led by the receiving site’s validation group.

Lessons learned include:

• Donor companies find it very reassuring to have a fully documented set of risks and responsibilities.
• By agreeing on the mechanism/areas of responsibility upfront, issues during transfer can be quickly resolved.
• Improved upfront detailing of assumptions that lie behind the risk assessment can reduce the number of risks that are dealt with via the silver bullet mechanism and thus reduce the time associated with their assessment.
• Many clients have their own donor-side tech transfer risk assessments. By agreeing on the mechanisms and definitions at the start of the tech transfer, the Alkermes risk assessment has been used to “kill two birds with one stone” with the client taking or referencing the joint risk assessment in their internal systems.
• Involving all stakeholders from both sides from the outset is invaluable. The process and any differences in the processes between the donor and recipient sites are well understood long before the critical process qualification stage. This can make the review and approval of validation protocols, master batch records and change controls much more efficient.
• Dedicating time to the risk assessment is key — the first time a new process, piece of equipment or a commercial partner is involved in a risk assessment is time consuming. Subsequent transfers can leverage the risk assessments developed in previous transfers. Eventually, a library of risk assessments covering all key unit operations is built.

A Solid Dose Case Study
1. Background
A large pharmaceutical company wished to outsource to Alkermes the commercial manufacture of a solid oral dose product, which had been in commercial production for more than five years. Alkermes had previous experience in the core technologies and processes involved. This was the donor’s first major tech transfer to Alkermes.

2. The Challenge
The donor’s desire was to minimize regulatory changes, so the donor equipment train was to be replicated wherever possible. This required the purchase, installation and qualification of new equipment at the Alkermes site. Some of this equipment was at a working scale new to Alkermes.

Existing Alkermes equipment was to be employed for one core unit operation. This required a process scale change from the donor site.

A lean approach to the tech transfer was agreed upon, i.e., only one active engineering batch was to be manufactured prior to process validation.

The regulatory filings were the responsibility of the donor company. Minimal development data or product history was shared with the recipient site.

3. The Approach – Joint Risk Assessment
The first round of risk assessment was performed based on the client’s transfer plan and process knowledge at Alkermes.

It was agreed that all risks identified must be closed out by one of the following means prior to proceeding to process validation:

• Donor and Alkermes deem the risks to be acceptable.
• Donor and Alkermes deem additional data is required. Donor to provide/facilitate data gathering.
• Donor and Alkermes deem additional data is required. Donor has existing supporting data. Donor declares the risk is acceptable.
• Alkermes deems the risk is unacceptable. Donor prepared to accept risk.
• Donor and Alkermes deem the risk to be unacceptable. Further work is required to close out.

4. Risks identified
Some 250 risks were identified at the initial brainstorming session and presented to the donor. Of these, 195 were deemed to be high risk, as they directly impacted a CQA at the end of the risk ranking process.

On completion of the risk ranking and silver bullet process with the donor company, 70 risks retained a high-risk designation and were progressed to FMECA. These risks included the risks associated with the single active engineering batch approach. The FMECA process identified the engineering studies required. This included a short placebo manufacturing campaign to support the lean active engineering campaign.

The risk assessment was revisited and updated at the end of the placebo engineering trials, i.e., before the active engineering demonstration batch and again on completion of the demonstration batch. At this point, zero technical and five business risks remained identified as high risk. All quality risks had been mitigated via the additional engineering studies and controls identified through the various iterations of the risk assessment. The remaining business risks were all deemed acceptable by the donor as they related to process historical data readily available to the donor but not shared with the Alkermes team. It was assessed, agreed and documented that the five business risks had no quality or patient safety impact (Figure 1). It was agreed to progress to validation (Stage 2 PPQ) on this basis.

5. Conclusion – Successful Risk Assessment Completion
The time committed to jointly risk assessing the process played a lead role in the timely and successful tech transfer and validation of this product. The framework helped focus both parties throughout the tech transfer and was revisited many times to assist in technical decision-making. The work put into the risk assessment also fed directly into the development of the validation strategy for the product in question. The tech transfer was deemed to be a success by both parties.  

The framework was demonstrated to meet the user requirements suggested early in its development — it supported both parties in meeting their ICH obligations on risk assessment in tech transfers and confirmed the effectiveness of Alkermes’ QRM approach. The transfer was deemed to be efficient, and the framework was found to be easy to use.
Alkermes’ approach to risk assessment has evolved since the framework was first developed. These developments and the integration of the joint risk assessment with the continuous validation risk assessment approach will be discussed in the second article in this series.

In the coming months, the Alkermes Validation Group will publish a second article in this publication in which the further evolution of this approach and its integration with the continuous validation risk structures within Alkermes will be charted.