The State of Pharma Quality, GMP Certificates, November Pharma News Update

On October 10, 2022, version 12 of the EMA nitrosamines Q&A was published. This revision updates the answer to Q10, “Which limits apply for nitrosamines in medicinal products?” and adds a new Q&A 21, “What is the approach to control the presence of nitrosamines until a substance-specific AI is established?”

The new answer 21 states that if N-nitrosamines are identified without sufficient carcinogenicity data to derive a substance-specific limit for lifetime exposure as recommended in the ICH M7(R1) guideline, and the class-specific Threshold of Toxicological Concern (TTC) for nitrosamines of 18 ng/day is not used for controlling the levels of the nitrosamine in the finished product, an acceptable intake (AI) limit agreed by the Non-clinical Working Party (NcWP) and adopted by the CHMP is required to decide on control options for the nitrosamine in the finished product.

The Q/A allows the adoption of a temporary AI (t-AI) of 178 ng/day, which is more achievable compared to the original 18 ng/day and provides flexibility until the final AI is announced.

In practice, this means that when competent authorities are notified about a product containing a new N-nitrosamine exceeding the TTC limit of 18 ng/day, no market actions may be required for batches with N-nitrosamine levels ≤178 ng/day pending the agreement of the AI, but this limit can be used for only 12 months and will need additional consultation if used further. Also, the Q/A highlights that it should not be used as a target of development.

NSF experts have consistently looked at issues related to nitrosamines. NSF Associate Paul J. Cummings presented on the issue in the webinar below.

Revision 2 of ICH Q5A achieved step 2b approval on September 29, 2022, and now moves to step 3, public consultation. The revised guideline adds key coverage of new product types that are amenable to viral clearance, like genetically engineered viral vectors and viral vector-derived products, such as virus-like particles, protein subunits, and nanoparticle-based vaccines and therapeutics.

A new Section 7 provides viral safety points to consider for continuous manufacturing, including when batch processes could suffice as scale-down models, which should be read in parallel with the new ICH Q13 guideline on continuous manufacturing.

On October 10, the EMA and HMA launched a joint consultation by publishing a new draft document titled “Data Quality Framework for EU Medicines Regulation.” The consultation ends on November 18, 2022.

This draft framework provides general considerations on data quality that are relevant for regulatory decision-making and definitions for data dimensions and subdimensions, as well as their characterization and related metrics. It provides an analysis of what data quality actions and metrics can be put in place in different scenarios and introduces a maturity model to drive the evolution of automation to support data-driven regulatory decision-making.

The document is intended to be an overall umbrella from which more focused recommendations can be derived for specific regulatory domains with specified metrics and checks.

The draft DQF is comprised of two parts:

1. The general framework is designed to provide a coherent approach to data quality that can encompass a broad range of data types and is able to be extended to novel use cases.
2. The specialization framework specializes and eventually extends generic recommendations to cater to specific data types or regulatory questions.

The draft ends by providing a list of the special areas of regulatory decision-making that the framework can be applied to:

• bioanalytical omics data,
• animal health data,
• preclinical data (cell-based and animal-based laboratory data),
• spontaneous adverse drug reporting data, and
• chemical and manufacturing control data.

The U.S. FDA has issued guidance titled “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules.” This guidance revises the guidance of the same name issued in June 2015 to clarify that the largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a standard 00 size. This guidance also includes updated references.

The introduction to this guidance states that the FDA is “concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors.” Consequently, the FDA is “recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates.”

This guidance does not apply to approved ANDAs (generic drugs) already on the market. However, if the FDA believes that the size or shape of a product poses a risk to public health, then they will contact the ANDA holder to request modifications.

Related Content: Lapses in Compliance — Overcoming the Risks of Cost Cutting for OTC Drug Manufacturers

Is cost cutting affecting compliance? Maxine Fritz discusses how lack of regulation in the OTC industry has led to manufacturer cost cutting and lapses in GMP compliance. Find out how OTC manufacturers can overcome these challenges to ensure that they meet all relevant regulatory requirements.

The U.S. FDA is updating two of its drug compliance programs that provide guidance and instructions to FDA staff for obtaining information to help fulfill agency plans in the specified program area. Both updates, which become effective from October 17, 2022, now include ICH Q9, Q10 and Q12; the control of nitrosamine impurities; and alternative tools for evaluating facilities.

CPGM 7356.002 Drug Quality Assurance

This update adds two new attachments: A on Remote Regulatory Assessments and B on indicators of an Advanced Quality System.

Attachment A on Remote Regulatory Assessments (RRAs) states that they are used in place of or in advance of inspections, which has allowed the FDA to remotely evaluate drug manufacturing establishments to mitigate risks, but are not the same as regulatory inspections.

Attachment B on indicators of an Advanced Quality System is interesting in that this is likely to play a part in the FDA’s Quality Management Maturity (QMM) project.

CPGM 7346.832 New Drug Evaluation

This revision has added a fourth objective for pre-approval inspections (PAIs), which is “Commitment to Quality in Pharmaceutical Development.” Unfortunately, it does not indicate what the FDA will be looking for to meet this objective, but perhaps part of the answer can be found in Attachment B of CPGM 7356.002.