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By Paul Hurley, Associate Director, Product Development and Scale-Up, Alkermes Pharma Ireland Ltd.
A Solid Dose Case Study
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:
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.
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