WHAT IS QUALITY IN MEDICINES?

WHAT IS QUALITY IN MEDICINES?

THE SITUATION WORLDWIDE AND IN TURKEY

Prof. Dr. F. Cankat Tulunay

No advanced regulatory system allows a medicinal product to enter the market without undergoing quality control in a meaningful sense. However, in some countries, quality evaluation prior to marketing is not conducted with sufficient depth to reflect real clinical and pharmaceutical performance, and is effectively deferred to post-marketing surveillance. This approach is incompatible with patient safety and the ethical principles of regulation.

The Concept of Quality in Medicines

The concept of “quality in medicines” is not limited to the mere presence of the correct active pharmaceutical ingredient. According to international regulatory authorities (EMA, FDA, WHO), quality encompasses the entirety of pharmaceutical attributes that ensure a medicinal product reaches the patient in a safe, effective, and predictable manner. In modern regulatory science, medicinal product quality rests on three fundamental pillars:

• Pharmaceutical quality
• Safety
• Efficacy

These three pillars are inseparable, particularly for generic products and fixed-dose combination medicines. If pharmaceutical quality is inadequate, clinical outcomes may differ even when a product is theoretically bioequivalent.

What Are Disintegration and Dissolution?

Disintegration refers to the physical breakdown of a solid dosage form (tablet or capsule) upon contact with gastrointestinal fluids. The test assesses whether the dosage form disintegrates within a specified time. However, a critical limitation must be emphasized: disintegration does not guarantee absorption or adequate bioavailability. A tablet may disintegrate rapidly, yet the active substance may fail to dissolve or reach a particle size suitable for systemic absorption.

Dissolution testing measures the extent and rate at which the active substance dissolves from the pharmaceutical formulation within a defined time frame. In oral solid dosage forms, dissolution is considered an indirect indicator of bioavailability.

Dissolution testing evaluates solubility, release characteristics of the formulation, and manufacturing consistency. Nevertheless, its limitations are well defined: dissolution testing cannot replace bioequivalence studies. Both EMA and FDA clearly state that dissolution is a supportive quality test and cannot substitute for clinical bioavailability data.

Does Dissolution Demonstrate Quality?

A frequently implied assumption in Türkiye and some regulatory practices is: “If the product passes dissolution testing, it is clinically equivalent.” This assumption is scientifically incorrect. Numerous studies demonstrate that two products with similar dissolution profiles may exhibit different AUC and C_max values in humans. This is particularly relevant for:

• Poorly soluble active substances (BCS Class II and IV)
• Modified-release formulations
• Fixed-dose combination products

Therefore, dissolution is a quality control tool, not proof of bioequivalence.

In summary:

• Disintegration asks: Does the tablet break apart?
• Dissolution asks: Does the active substance dissolve?
• BA/BE asks: Is the drug actually absorbed in the human body?

If any one of these steps is missing, medicinal product quality cannot be considered complete. In fixed-dose combination products, the interaction between these steps becomes even more complex. Granting marketing authorization based solely on dissolution data for combination products is scientifically indefensible.

Substituting quality tests for BA/BE studies is not merely a technical error; it is an ethical issue. Patients are exposed to products with uncertain efficacy and safety, undermining patient protection, scientific integrity, and the societal legitimacy of regulatory systems.

What Does Medicinal Product Quality Truly Mean?

Quality is not a single “pass/fail” result. It requires consistent fulfillment of the following throughout the product lifecycle:

• Identity and content accuracy: Is the active substance correct? Is the dose accurate? Is the impurity profile acceptable?
• Performance: Does the product behave as intended in its pharmaceutical form (especially release and dissolution behavior)?
• Consistency and batch reproducibility: Can the same quality be achieved across all batches (GMP compliance, process control, stability)?

Quality is therefore not simply “correct labeling,” but the combined result of pharmaceutical performance and manufacturing system maturity (GMP, validation, stability, change control). This is the core of EMA/FDA/ICH quality philosophy (CTD Module 3 combined with inspection and lifecycle oversight).

When Should Quality Control Be Performed?

From a scientific and ethical standpoint, quality must be sufficiently demonstrated prior to marketing authorization and continuously verified thereafter. In practice, however, regulatory approaches differ substantially among countries.

Advanced Regulatory Systems (EMA, FDA, PMDA)

Pre-Marketing Controls:
CMC documentation, stability, dissolution, and BA/BE studies are fundamental requirements. The purpose of pre-marketing evaluation is to prevent inherently risky products from entering the market. However, a major limitation remains: dossiers often demonstrate “paper quality” that may not fully reflect real-world performance.

Post-Marketing Controls:
Post-marketing surveillance is the most critical phase of modern regulation. This includes linking pharmacovigilance signals to quality concerns, targeted GMP inspections, and random market sampling for dissolution and quality testing.

Many medicines in the US and Europe have been withdrawn years after approval due to quality defects, demonstrating that pre-marketing controls alone are insufficient.

The ethically sound approach recognizes medicinal quality as a dynamic process requiring continuous monitoring. Reliance solely on pre-approval testing risks overlooking:

• Manufacturing site changes
• Raw material sourcing
• Scale-up challenges
• Progressive quality degradation

For this reason, EMA, FDA, and WHO regard continuous quality surveillance, post-marketing sampling, and transparent recall mechanisms as essential components of regulation.

Bioavailability and Bioequivalence in Fixed-Dose Combination Products

Bioavailability (BA) and bioequivalence (BE) are foundational concepts in the approval of generic and therapeutically equivalent products. Bioequivalence is defined as the absence of a clinically meaningful difference in absorption rate and extent (AUC and C_max) between two products administered at the same molar dose (1).

This principle applies not only to generic-reference comparisons but also to fixed-dose combination (FDC) products. FDCs are not simple sums of their components; they represent new pharmaceutical entities with distinct pharmacokinetic and pharmacodynamic characteristics (2).

EMA Position

The European Medicines Agency explicitly states that fixed-dose combination products require appropriate pharmacokinetic, pharmacodynamic, and clinical justification. Previous data on individual components cannot substitute for evaluation of the combination itself.

FDA Position

FDA guidance states:
“Bioavailability and bioequivalence data should generally be provided for fixed-dose combination products unless adequately justified otherwise.”
This confirms that automatic BE waivers for FDCs are scientifically unacceptable.

WHO Position

WHO technical reports emphasize that fixed-dose combinations may exhibit bioavailability characteristics different from their individual components, mandating BA/BE data for patient safety.

Turkish BA/BE Regulation (TİTCK)

Türkiye’s regulation on BA/BE explicitly aims to prevent therapeutic failure and toxicity:

Article 1:
“The purpose of this Regulation is to define measures to prevent risks arising from insufficient treatment or increased toxicity by evaluating bioavailability and bioequivalence of pharmaceutical products.” (7)

Article 2:
“This Regulation covers the principles regarding evaluation of pharmaceutical products in terms of bioavailability and bioequivalence.” (7)

By definition, fixed-dose combinations fall under “pharmaceutical products” and should not be exempt from BA/BE assessment.

Naproxen + Codeine: A Türkiye-Specific Paradox

The naproxen sodium + codeine combination is not widely approved internationally. Despite the absence of FDA approval and EMA authorization, it received generic marketing authorization in Türkiye without combination-level BA/BE studies.

This raises serious scientific concerns. Naproxen has predictable pharmacokinetics, whereas codeine is a CYP2D6-dependent prodrug with high interindividual variability. Combined administration may yield unpredictable clinical outcomes.

The key question remains:
How can a combination rejected by leading regulatory authorities be approved as a generic medicine in Türkiye without its own BA/BE data?

Political and Ethical Considerations

BA/BE exemptions may appear to facilitate access to generics in the short term, but they pose long-term risks to patient safety, therapeutic effectiveness, and scientific transparency. Licensing products without adequate pharmacokinetic data exposes patients to uncertainty and violates the ethical principles of non-maleficence and scientific integrity (12).

Global Regulatory Comparison

No serious regulatory system permits medicines to enter the market without quality control, but the depth of pre-marketing requirements varies significantly:

• USA (FDA): Risk-based oversight; BE required for most generics; foreign facilities may remain uninspected for years.
• EU (EMA): More conservative and systematic; GMP documentation mandatory; stricter FDC justification.
• UK (MHRA): Maintains EU-level standards.
• Japan (PMDA): Extremely stringent; many generics cannot enter the market.
• India (CDSCO): Weaker pre-marketing controls for domestic market; BE not always required.
• China: Rapidly improving but heterogeneous.
• Türkiye: Approximately 22,151 licensed medicines; ~7,172 actively marketed. In 2024, 467 new licenses granted.

Public data on annual laboratory analyses remain incomplete, limiting transparency.

Conclusion

International literature and EMA, FDA, and WHO guidance clearly support independent BA/BE evaluation for fixed-dose combinations. While Turkish legislation aligns with this principle, practical exemptions—such as the naproxen + codeine case—raise serious scientific and ethical concerns.

Reevaluation of BA/BE exemptions in fixed-dose combinations is essential to align Türkiye’s regulatory practice with international standards, patient safety, and scientific transparency.

References

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4. European Medicines Agency. Guideline on the investigation of bioequivalence. London: European Medicines Agency; 2010 (revised 2018).
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6. World Health Organization. WHO Technical Report Series No. 929: Guidelines on registration of fixed-dose combination medicinal products. Geneva: World Health Organization; 2005.
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