Significance of Inspection in the Formulation Industry:

A Study on various Defects and its Remediation

Abinaya G.¹, Jyodish S S.², Ashlesh Prabhu.³, Mahendra Joshi.⁴,

Kiran Kumar H.⁵, Girish Pai K.^1*

¹Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal, Karnataka, India – 576104.

²Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal, Karnataka, India – 576104.

³Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal, Karnataka, India – 576104.

⁴Research and Development, IDRS Labs Pvt. Ltd., Bangalore, Karnataka, India.

⁵Corporate Development, Ingenus Pharmaceuticals LLC, 100 Ford Rd, Denville, New Jersey.

*Corresponding Author E-mail: girish.pai@manipal.edu

ABSTRACT:

Blister packaging is a preferred system in the pharmaceutical industry for protecting dosage forms and promoting patient compliance, yet it is susceptible to manufacturing defects that can compromise product quality and safety. This study examines common defects such as sticking, binding, black spots, twinning, tablet breakage, and contamination, identifying their probable root causes and proposing remediation strategies. The scope includes analysis of case studies involving missing units, damaged tablets, and visible contamination, alongside evaluation of inspection methods. Key findings indicate that inadequate in-process quality checks (IPQC), poor equipment maintenance, environmental deviations, and insufficient operator training are primary contributors to critical defects. The results emphasize that strengthening in-process quality checks, implementing preventive maintenance, optimizing process parameters, and improving environmental controls can significantly reduce defect incidence. Furthermore, integrating advanced technologies such as real-time monitoring, predictive analytics, and machine learning-based defect detection enhances inspection efficiency and defect prevention. The study concludes that a proactive, technology-driven quality assurance approach is essential to eliminate blister packaging defects, ensure regulatory compliance, maintain therapeutic efficacy, and safeguard patient health. Continuous improvement in inspection and process control not only prevents recalls but also sustains market credibility and public trust.

KEYWORDS: Pharmaceutical defect, In-process quality checks, Blister packs, Patient safety, Regulatory compliance.

INTRODUCTION: 

Packaging is defined as a technique which provides isolation of pharmaceutical products from the time of development in a unit till its use¹. Pharmaceutical packaging is defined as the cost-effective methods of delivering the product's display, security, identification, information, ease of use, conformance, integrity, and stability². Every product shipped from the manufacturer to the final consumer needs to be appropriately packaged to shield it from external factors. In the same context, pharmaceutical items require packaging that is better than other products to meet their primary requirements, which include safety, efficacy, purity, integrity, and uniformity, to show a good shelf-life stability profile³. Non-compliance with packaging regulations can have serious effects on organizations as well as patients⁴.

Figure 1. Types of pharmaceutical packaging for tablets and capsules⁵

Figure 1. Blister packaging is growing in popularity as customers and pharmaceutical manufacturers learn about its advantages. Blister packs are portable, prolong the shelf life of medications, and assist patients in adhering to their prescribed dosages. Blister packaging proponents in the US outline five reasons why blister packaging is superior to traditional packing.

· Product integrity

· Protection

· Tamper evidence

· Decreased risk of unintentional abuse patient compliance⁶

Types of defects inside blister pack:

1. Sticking:

One of the most prevalent tablet flaws is sticking. Instead of being ejected easily, it occurs when the tablet material sticks to the punches and dies. This may result in problems with tablet ejection, tablet damage, and variations in the general quality of the tablets.

Reasons:

· The compression tooling and tablet material are not adequately lubricated.

· Some formulas include sticky or hygroscopic substances.

· The surface finishes of the dies and punches are harsh.

· Insufficient dwell time causes the granules to not sufficiently consolidate.

· Uneven compression force distribution results from misalignment or worn-out tooling.

Remedies:

· Choose lubricants that are appropriate for the compression tooling and formulation.

· By changing the composition or adding appropriate excipients, you can vary the formulation.

· Regularly check, clean, and maintain the equipment.

· Optimize compression force and dwell time.

· Replace worn-out tooling or perform routine tooling calibration⁷.

2. Binding:

Another typical issue with tablets is binding. During the compression process, it describes the unwelcome adherence of granules to the die surface. Tablet ejection issues decreased production efficiency, and subpart tablet quality can all be caused by binding.

Reasons:

· One common cause is improper lubrication between the dies and the grains.

· The tablet substance may adhere to the dies if there is too much moisture present.

· The granules are sticky and prone to adhesion because of hygroscopic ingredients.

Remedies:

· Lubricate the dies and tablet material with the appropriate lubricants.

· Keep an eye on and regulate the formulation's moisture content.

· Utilize non-hygroscopic excipients and modify the formulation's composition.

3. Black spots:

The term "black spots" describes the dark or black dots or specks on the tablet's surface. These patches are seen as flaws and may detract from the tablets' overall quality and look.

Reasons:

· The raw ingredients used to make tablets contain impurities or foreign particles.

· The manufacturing environment, compression tooling, and equipment are well-cleaned.

· Agglomeration is the result of inadequate lubricant mixing.

· There is improper granulation in the tablet composition.

· Black stains or discoloration are the result of formulation ingredients oxidizing or being exposed to adverse environments.

Remedies:

· Make use of premium, contaminant-free raw materials.

· Keep the manufacturing areas, tooling, and equipment clean on a regular basis.

· To ensure that the lubricants in the formulation are properly dispersed, optimize the blending procedure.

· Keep an eye on and manage the granulation process.

· Keep completed pills and raw materials in the proper storage conditions.

4. Twinning:

One of the most prevalent tablet issues is twinning. It appears as a combination of two separate tablets. When two tablets adhere to one another while being compressed, this is known as twinning.

Reasons:

· The punches, dies, and tablet material are not sufficiently lubricated.

· Tablets with high porosity are the result of improperly granulated formulations.

· Twining is more common on tablets with parallel or flat faces.

· Tablets that experience inconsistent compression force combine rather than form separately.

· The tablet press's ejection mechanism isn't operating at its best.

      Remedies:

· Make sure that the compression tooling and tablet substance are properly lubricated.

· To lessen tablet porosity, keep an eye on and manage the granulation process.

· Utilize the design elements, like the curvature or beveled edges, to make it easier to separate the tablets.

· Throughout the tableting process, keep the appropriate compression force.

· Verify that the ejection mechanism is operating correctly⁸.

5. Tablet breakage:

This flaw occurs when tablets shatter when the pan is being loaded when they are tumbling in the pan, when the coating process is underway, or when the coating pan is being unloaded.

Reasons:

· The tablets are too fragile.

· Poor coating tablet form.

· A poorly designed baffle.

· Pan speed is excessively high.

· Taking tablets out of the coating pan and loading them.

· The formula uses less binder.

Remedies:

· Modify the parameters for core compression.

· Make use of the right tablet shape.

· Modify the baffle's design.

· Lower the pan speed.

· Load and unload tablets with caution.

· Make use of the ideal amount of binder⁹.

There are some case studies that have defects inside blister packets during manufacturing.

Case study 1 – Missing capsule and black particle on blister^10,11

Dosage form: Hard gelatin capsules

Generic Name: Hydroxyurea capsules

Therapeutic category: Anti-cancer¹²

Defects:

· Black particle found in the blister pack (Bottom right side)

· Missing capsule in the assigned blister pocket

Figure 2. Evidence showing missing capsule and prominent black particle (bottom right side besides capsules)

Category of complaint:

Critical¹⁷

Probable root causes:

· Poor quality control and testing

· No adequate in-process quality checks and no mechanisms to reject such blisters.

· 100% inspection was not carried out.

· Inadequate machine setup or worn-out machine parts used for blister packaging operation.

· Vendor audits and requalification.

Remediation:

· Quality control sampling and testing to be made more stringent.

· Review the packaging operation to ensure correct machine setting, replace worn-out parts of the packaging machine and install camera-based inspections.

· Institute practice of in-process 100% visual inspection before cartooning.

· Perform vendor audits and discuss the presence of black particles in foil/poly vinyl chloride films.

· Review area cleanliness of the packaging operation and thorough check by quality assurance personnel before line clearance activity.

Clinical Significance:

· The patient may not consume the dose due to contamination/presence of black particle on   the blister.

· Due to one missed capsule in blister, patient may be causal in completing the treatment regimen as defined by physician.

Case study 2 – Half- broken uncoated tablet within blister pocket^10,11

Dosage form:

Uncoated tablets

Generic Name:

Paracetamol tablets

Therapeutic category:

Analgesic (pain reliever and fever reducer)¹³

Defects:

Only half of the round shaped tablet found within an intact blister packet

Figure 3. Half tablet within intact blister packet

Category of complaint:

critical¹⁷

Probable root causes:

· In-process quality checks was not done adequately

· Intermediate product line clearance was not properly performed.

· Final quality assurance approval was given without a proper inspection before sampling of the batch.

Remediation:

· In-process quality check should be done vigilantly.

· Every blister pass through the weight check in the packing line, which should be one of the In-process quality checks and be a part of the batch packing record¹⁴.

Clinical Significance:

· Patient compliance will decrease and this will directly affect the therapeutic outcomes due to psychological effects.

· Altered therapeutic efficacy due to a low amount of active ingredients in the half-broken tablets.

Case study 3 – Soiled, damaged, soft gelatin capsules within blister packet^10,11

Dosage form:

Soft gelatin capsules

Generic Name:

Methylcobalamine, alpha lipoic acid, pyridoxine hydrogen chloride and folic acid soft gelatin capsules.

Therapeutic category:

Nutraceutical supplement¹⁵

Defects:

Soiled and damaged soft gelatin capsules found inside blister pockets.

Figure 4: Soiled and damaged soft gelatin capsules in the first two blisters and good blister at bottom

Category of complaint:

Critical¹⁷

Probable root causes:

Unwanted adverse drug reactions may result due to degraded active ingredients if patient consumes the defective capsules.

Remediation:

· Well defined cleaning procedures for rollers and inspection belts.

· Standard operating procedure (SOP) for preventive maintenance program

· Maintaining environmental conditions as per product requirements

· Strength of gelatin film to be defined in raw material specification and storage time for raw material to be monitored.

· Hourly in-process checks to monitor critical process parameters¹⁴.

Clinical Significance:

Inadequate dosing to patience and lack of efficacy. Improper dose of drug may affect the therapeutic efficacy, Non-compliance of label claim leading to legal complications and Poor market credibility

Case study 4 – Chipped uncoated tablet within blister packet^10,11

Dosage form: Uncoated tablets

Generic Name: Gliclazide and metformin hydrochloride tablets

Therapeutic category:

Antidiabetic agent¹⁶

Defects: Chipped (broken edge) caplet found inside blister pocket.

Figure 5: Chipped Caplet found within blister pocket (bottom: 2^nd tablet edge)

Category of complaint:

Critical¹⁷

Probable root causes:

· Poor granular property leads to breakages of tablets.

· More hold time of blend also leads to defective tablets.

· Inadequate design of tablet tooling.

· Improper storage practices of bulk tablet per container.

· Untrained operators handling the products.

· Fine tuning of compression equipment setting like feed frame etc.

· Inadequate environmental conditions.

Remediation:

· Controls of tablets storage per container.

· Effective supervision and training of operators.

· Good blend properties / consistent blend quality.

· Maintaining required temperature and relative humidity conditions.

· Preventive maintenance plans for change parts.

· Monitoring of manual versus automated controls.

· Automated inspection procedure in case if tablets are subjected for 100% inspection.

Clinical Significance:

Poor quality and low dose. Altered therapeutic efficacy due to low strength of active ingredient in chipped tablets and may results in increased glucose level in the patients.

CONCLUSION:

Blister packaging remains a cornerstone in pharmaceutical product protection, preserving stability, integrity, and patient adherence. However, the case studies show that even small deviations in equipment maintenance, process control, and inspection rigour can lead to serious defects, which directly endanger patient safety, treatment effectiveness, and brand credibility. To reduce such risks, packaging operations must maintain validated processes, thorough in-process quality checks, strong documentation, and traceable corrective actions, as required by regulatory frameworks like Good Manufacturing Practices (GMP) and specific requirements from organizations like the USFDA and EMA. Advanced inspection technologies, such as real-time vision analytics, predictive maintenance algorithms, high-resolution camera-based systems, and machine learning-driven defect classification, can be integrated to provide a revolutionary opportunity to go beyond baseline compliance and move towards proactive defect prevention. While the manufacturers can accomplish compliance and establish new standards for product safety and dependability by integrating these technologies into a framework of risk-based quality management and continuous improvement. This strategy ensures that blister packaging functions as a vital safety measure for patient health and confidence worldwide, rather than just a container, in line with the growing regulatory emphasis on Quality by Design (QbD) principles.

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Received on 17.04.2025      Revised on 16.08.2025

Accepted on 23.10.2025 Published on 08.11.2025

Available online from November 13, 2025

Research J. Pharmacy and Technology. 2025;18(11):5539-5544.

DOI: 10.52711/0974-360X.2025.00798

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