December 2021

· 9 min read

Top 10 FDA Inspection Findings & More, December 2021 Pharmaceutical News Update

Dr. Peter Gough looks at December 2021 news updates in the pharma sector, including the top 10 FDA inspection findings and more.
Pharmaceutical drug production - pharmaceutical drug | NSF International

The December 2021 Pharmaceutical News Update looks at a range of issues impacting the life sciences sector and its professionals. Dr. Peter Gough, Vice President for Pharmaceutical Services, EMEA, at NSF International, looks at:

This edition includes:

  • The top 10 FDA inspection findings for 2021.
  • The EMA concept papers on the revisions of GMP Annexes 4 and 5.
  • The European Commission request for an investigation into the technical purpose of titanium dioxide in medicinal products.

Our global pharma biotech team of consultants and trainers can assist your company in ensuring compliance with ever-changing legislation. Contact us by completing the “Ready to Begin the Process” web form at the end of this page.

Revision of GMP Annexes 4 & 5

On November 9, 2021, the EMA published concept papers jointly with PIC/S proposing to revise GMP Annexes 4 and 5, which relate to the manufacture of veterinary medicinal products.

Since the annexes were first published in the 1990s, the manufacturing and regulatory landscape has changed significantly. These revised annexes are required to reflect this shift in the technical/scientific and regulatory environment. The main reasons for updating these annexes are to:

  • Facilitate the implementation of the principles set by ICH guidelines Q8, 9, 10 and 11 and ad hoc VICH guidelines.
  • Extend the underlying concepts to include new areas of technology (e.g., novel therapy products), new processing methods and new products not previously covered.
  • Clarify areas highlighted as ambiguous due to the age of the documents.

Also, there is no universal legislative requirement for GMP manufacture of medicines for use in veterinary clinical trials in EU or PIC/S member states. However, national legislation in some countries may require this. Therefore, it is suggested that the revised guidance acknowledge this fact and clarify that, where required nationally, the guidance may be applicable as appropriate to the manufacture of investigational veterinary medicinal products.

Comments on these two concept papers should be submitted by January 9, 2022.

The Top 10 FDA Inspection Findings for FY 2021

An analysis of FDA inspection findings shows that there was a dramatic reduction in observations in fiscal years 2020 and 2021 due to COVID-19 travel restrictions. The FDA virtually ceased inspections in the middle of FY 2020 and, since then, has conducted only inspections that were “mission-critical.”

While the FDA started to conduct remote record reviews instead of inspections to assess manufacturing facilities from mid-FY 2020 to 2021, the agency does not call these reviews “inspections” and, therefore, does not include their findings among its inspectional observations.

The top 10 FDA inspection findings for FY 2021 were not significantly different from previous years, as these results show:

  • QC unit failed to meet its responsibilities.
  • Failure to adequately investigate OOS results and other deviations.
  • Absence of written procedures for production and process control.
  • Lack of adequate controls in laboratories.
  • Inadequate cleaning, maintenance and sanitizing of equipment.
  • Lack of controls for authorization of personnel to access master production and control records.
  • Use of equipment that was not appropriately designed, of adequate size or suitably located.
  • Failure to establish, write and follow procedures for preventing microbiological contamination of sterile drug products.
  • Failure to routinely calibrate, inspect and check equipment.
  • Workers lacking training in GMP for the operations they perform.

Lack of training or a failure to stay up to date on legislation and changes to best practices can negatively impact companies.

Martin Lush looks at the issue of training in this brief video.

Analysis of the Technical Purpose of Titanium Dioxide in Medicinal Products

For some time, there has been concern over the safety, including the possible genotoxicity, of titanium dioxide, or TiO2. On May 6, 2021, the European Food Safety Authority (EFSA) published its opinion on the safety of TiO2 as a food additive, recommending that based on all currently available evidence, TiO2 can no longer be considered safe when used as a food additive.

Following the EFSA’s recommendation, on May 17, 2021, the European Commission (EC) requested that the European Medicines Agency (EMA) analyze the technical purpose of titanium dioxide in medicinal products. The EC asked the EMA to assess alternatives to replace it without negatively impacting medicines’ quality, safety and efficacy. Furthermore, it has requested that considerations be taken into account to define a transition period for phasing out this excipient.

Titanium dioxide is widely used as an opacifier and colorant in pharmaceuticals. It is monographed in the European Pharmacopoeia and currently considered suitable for use in medicinal products as an excipient. It is used frequently in oral solid dosage forms (e.g., tablets, soft capsules, hard capsules, and granules/powders for oral solutions and oral suspensions). Titanium dioxide is also used in oral semisolid dosage forms (e.g., oral paste and oral gel). It is present in several essential human medicines, including antidiabetics, antibiotics and others, as well as in several veterinary medicinal products.

On September 8, 2021, the EMA published its final feedback to the commission on the impact of the removal of titanium dioxide from the list of authorized food additives in medicinal products. The EMA feedback offered the following conclusions:

  • To date, no single material has been identified that provides the same combination of properties unique to TiO2 (e.g., opacity, enhancing contrast, inertness, protection from UV light and finish/smoothness of the resulting product). Separating the different functionalities of TiO2 for those medicinal products in which it serves more than one purpose is difficult or may not be possible at all.
  • Possible alternatives identified so far include calcium carbonate, talc and starch. Several disadvantages exist with these alternatives (e.g., inability to obtain sufficiently thin films, supply chain issues and mined materials with associated elemental impurity risk).
  • The direct and indirect impacts on human and veterinary medicine use are expected to be aggravated in the scenario, in which Europe would be the only region globally to ban TiO2 as an excipient in medicines. To do so would require the pharmaceutical industry to develop new formulations for the majority of oral solid dose products, potentially for the EU only, with titanium dioxide continuing to be used in the majority of medicines globally.
  • An acceptable transition period for phasing out TiO2 in all or specific uses in medicines covered by the scope of coloring matters is currently difficult to envisage or estimate. The time needed to reformulate each product could be several years, depending on the level of formulation and studies required, followed by the necessary regulatory procedures for assessment and approval.
  • Considering the scale of the use of this excipient, the time and costs involved in reformulation, and the volume of products impacted, any requirement to replace TiO2 in medicines will almost certainly cause medicine shortages and discontinuations or withdrawals of medicines from the EU/EEA market, with significant implications for patients and animals.

The EMA concluded that it is not feasible for the replacement of TiO2 to be achieved without a negative impact on the quality and availability of medicines in the EU/EEA.

Given the volume of products potentially impacted by a decision to require the removal of TiO2 in medicinal products, it is considered highly likely that many such products may be discontinued, and particular concerns arise about certain classes/types of products (e.g., pediatric, orphan, low sales volume, etc.).

Industry estimates for the reformulation of individual products vary from three to five years, and regulatory estimates for the approval of individual changes range from three months to a year. Considering these factors and the volume of products involved, the industry estimates of seven to 12 years are a reasonable time frame.

The EMA’s Quality Working Party concluded that a transition period of 10 years or even longer would be required for the phasing out of TiO2 in medicines.