Did you know that Chapter 1 of the NCF is currently under review? While the pharmaceutical regulatory framework is sufficiently specific, there are still technical details to address, as highlighted in the public consultation open until December of this year for Chapter 1 of the NCF.
In recent years, we have seen regulations increasingly adopt a broader and stronger approach to risk management, from the ICH Q9 (R1) revision to the new Annex 1 for sterile product manufacturing. This is why the revision of Chapter 1, being the basic guide on which the implementation of a quality system is based, is an expected development aligned with risk management.
A key concept introduced in this revision is the assurance of medicine availability. This aligns with the need to mitigate the risk of medicine shortages and outlines concrete actions to implement within the quality management system.
The rationale for the change can be based on two aspects. The first concerns internal factors, meaning those entirely under the organization’s control, where knowledge-based risk management is the key tool to predict situations that could compromise product quality and potentially cause supply issues. The second focuses on external factors, i.e., risks arising from third parties, such as raw material suppliers and CMOs, who are direct contributors to the quality and continuity of the final product.
Setting aside external risks, which are mitigated through supplier qualification and monitoring, the proposed modification of Chapter 1 continues to expand the requirements for the key knowledge management tool of the product: the Product Quality Review (PQR).
Key highlights of the proposed changes include:
1. Cumulative PQRs
It is required to perform PQRs using cumulative data, incorporating information from previous years in statistical analyses. This directly affects the statistical significance of process capability parameters, trends, and OOS predictions, thus strengthening conclusions about process control and pharmaceutical product quality. Comparisons across years must also be included, enabling assessment of process evolution over time.
This requirement is mandatory for products with a limited number of batches produced in a given period (often annually), while for others it is considered “useful.” Increasing the sample size is always scientifically beneficial for interpreting statistical results.
2. PQRs for all products
It has been common to exempt low-volume products from PQR exercises (e.g., fewer than three batches). However, the draft now requires PQRs for all products, even if no batches were manufactured in the period under review.
The exercise includes re-evaluation of independent aspects of batch production, such as stability data, returns, complaints, deviations, and regulatory items like variation status.
This requirement, while beneficial for understanding product lifecycle, impacts resources for large companies with extensive portfolios and especially medium-sized companies with low-turnover products. Quality managers must evaluate the time needed to comply with these new requirements.
3. Flexible review periods
To apply rational approaches across diverse pharmaceutical processes, the draft allows for non-annual review periods, provided proper justification is given (e.g., campaign duration).
4. Permitted product grouping
The draft allows grouping products for review, based on adequate justification and impact assessment. Examples include products with the same API or production line. Using worst-case or representative products is prohibited.
This could allow deeper analysis of a line producing multiple products with the same API but different doses, providing larger sample sizes for statistical studies.
5. Key factor in Quality Technical Agreements (QTAs)
When the manufacturer is not the Marketing Authorization Holder, PQR strategies (including grouping or review periods) must be agreed between both parties.
Looking beyond the new PQR requirements, the focus must be on data and statistical management. Reliable conclusions from PQRs depend on validated data collection and calculation systems. Authorities assume reliable process data systems exist, but in reality, many plants lack digital systems, requiring manual or semi-automated data transfer.
For this reason, internal evaluation of current PQR management is necessary, including:
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Assessment of digitalization and validation of pharmaceutical processes for reliable data
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Review of PQR policies and strategies
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Evaluation of resources needed for implementing changes
Conclusion
Implementing the proposed changes in Chapter 1 of the GMPs requires a thorough review of PQR policies to ensure process control and the ability to anticipate and react in time to reduce the risk of pharmaceutical product shortages.
