DDReg Pharma

An overview on some key regulatory challenges in API manufacturing

The regulatory landscape is consistently evolving as it faces ever-changing guidelines and regulations. On one hand, these patient-centric regulatory changes ensure that safe, efficacious, and high-quality pharmaceutical products reach the market. On the other hand, key stakeholders in the pharmaceutical regulatory environment face significant obstacles. Needless to say, these regulatory challenges are not limited to just one organization or country- they may be faced on a wider scale. Therefore, it is important to understand how and why organizations find themselves in these situations.
One such example are regulatory challenges that API manufacturers face- something that has occurred over a long period of time but are more predominant in current times. The API team at DDReg is one that is well-versed with some of the key regulatory challenges. Let us dive into some of the common ones:
Manufacturing API in accordance with Good Manufacturing Practice requirements.
One of the major challenges is meeting Good Manufacturing Practice (GMP) requirements during API production in accordance with the ICH Q7A guidance on ‘Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients’ [1]. Over the last few years, there has been a significant increase in FDA warning letters to API firms. Historically, API inspections are driven by DMF references made by NDA/ANDA/DMF/Export applications or CBER Drug Products for API users. The FDA decided to implement a risk-based inspection program to ensure GMP compliance was being met. Some of the key issues listed in FDA warning letters include:
  • Failure to maintain complete API records
  • Failure to control repackaging, relabeling, and holding operations to avoid mix-ups and loss of API identify
  • Lack of Quality Unit responsible for reviewing and approving cGMP documents & procedures, and assuring product quality
  • Failure to maintain complete data derived from laboratory tests
  • Inadequate investigations of critical deviations or failure of a batch to meet its specifications
Remediation for some of the above includes GMP compliant API training for employees to understand and implement quality management and control processes; commitment from management towards drug quality & safety; and data integrity with appropriate documentation and operational practices (if requested) for all materials that are produced or tested.
Choosing vendors for API.
API production capabilities as well as chemical & pharmaceutical industry is expanding worldwide keeping in line with the growth of the generic product landscape. International/foreign outsourcing of APIs have demonstrated growing concerns where despite diligent sourcing and supplier alliance, many things can go wrong such as failure to meet DMF specifications or outsourcing raw materials for API production that could damage production equipment where CMOs may either destroy the material or send it back thus contributing towards a prolonged project timeframe. Furthermore, navigating through unfamiliar markets can present challenges for API manufacturing firms; non-transparency along the supply chain with no provision to track quality assessments by API manufacturers can be a concern. Internal and regulatory audits. i.e., US FDA, should be conducted frequently that focusses on technical processes and internal audits; direct contact between API manufacturers and final formulators ensure that transparency in the supply chain is not compromised on. While outsourcing API is the preferred route, it is important to understand the API’s regulatory path and what results the potential supplier-partner relationship will bring.
To maintain market competitiveness, API manufacturers find themselves products large volumes of APIs at lower prices. And, with the prices of raw materials on the rise, API manufacturers face challenges in maintaining balance between market competitiveness and expenditure on raw materials. Furthermore, final formulators often find themselves having to prioritize having significant market share instead of profit. Indeed, it is important to remember that pricing does not mean everything especially the cost of failing to meet specifications will be a lot heavier.
References and Further Reading:

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