List of Potential Areas of Deviations in Pharmaceutical

The list of potential areas of deviations in pharmaceutical manufacturing covers materials, machines, processes, practices, documentation, test methods and specifications. A deviation is any departure from an approved procedure, process parameter, specification or instruction that can affect product quality or GMP compliance. It must be documented and investigated. The types of deviations in pharmaceuticals are described in a separate post.

List of Potential Areas of Deviations in Pharmaceutical

The potential areas of deviations in pharmaceutical manufacturing are given below. Each area is described in the sections that follow.

• Materials
• Equipment
• Process
• Practices
• Documentation Practices
• Test Methods
• Specifications

Materials

The following must meet their quality specifications before use in manufacturing:

• Raw materials
• Components
• Labels
• Packaging materials

Sometimes an unreleased material reaches manufacturing. Sometimes an unapproved labeling component is used in the labeling or packaging operation.

In either case, Quality Assurance (QA) must review the impact on the quality and compliance status of the product in detail before deciding the disposition of the batch.

Equipment

The sudden breakdown or malfunction of equipment is an unplanned deviation that can have an adverse impact on quality.

Equipment used in manufacturing, packaging or testing after its calibration due date compromises the compliance status of the product. A calibration deviation may show no apparent effect on the quality, safety or efficacy of the drug substance, but it still has compliance implications.

Replacing equipment with similar or comparable equipment in the middle of a manufacturing run is another possible deviation. The production team must document and justify the change when it happens, and the QA team must approve it beforehand.

Process

Deviation from process parameters and from process conditions can affect the product.

The following must stay within preset limits:

• Machine setup
• Mixing speed
• Drying temperature

Any departure from these limits is a deviation. It must be recorded, and the depth of the investigation depends on the impact on product quality, not on the distance from the validation data alone.

Production staff must maintain process conditions such as:

• Temperature
• Humidity
• Microbial quality of the environment

Any departure from their set limits is a deviation and could affect product quality. Normal variation within the limits is not a deviation.

Practices

Written procedures must be followed strictly, and a failure to do so is a deviation. Under 21 CFR 211.100, production and process-control procedures must be written and followed, and any departure must be recorded and justified. Schedule M and EU GMP set the same expectation.

For example, if staff do not follow the sampling procedure, the sample becomes suspect. Test data from that sample cannot support any quality decision.

Such a deviation requires re-sampling and retesting of materials, along with other corrective actions, including retraining of the employees. The audit check list for quality assurance can be used to review these practices.

Documentation Practices

Schedule M requires quality-related documents to be prepared, reviewed, approved and controlled under written procedures. The same expectation appears in EU GMP Chapter 4 and WHO GMP. The list of quality assurance SOPs shows the procedures that govern such documents.

These documents must be used in a consistent manner. If they are not, the inconsistency is a deviation that has to be explained.

Poor documentation practice can occur in any department, so every employee must be trained and retrained on it.

Test Methods

Analytical test methods are qualified for a given drug substance or product and a set of instruments. Under International Council for Harmonisation (ICH) Q2(R2), an analytical procedure is validated to show it is suitable for its intended use, so any departure from the approved procedure needs a documented investigation and justification before the result is used.

Any deviation from the approved analytical procedure needs a detailed investigation and also a sound scientific justification, and QA accepts the data for a quality decision only after both are done.

Some deviations are minor, yet these should be documented. Others can lead to a re-evaluation of the analytical method or the instrument used.

Sometimes a test must deviate from the approved method because the compendium has changed. In that case, the organization has not yet reviewed and approved the updated written procedure.

Specifications

Finished product specifications are based on sound scientific data and are a direct result of the behavior of the drug substance or product during development.

Raw material specifications follow the current pharmacopoeia, such as Indian Pharmacopoeia (IP), British Pharmacopoeia (BP) or United States Pharmacopeia (USP), or the approved supplier specification. Packaging component specifications follow the same basis.

A deviation from an approved specification means the material fails. QA then rejects the material or sends it for rework.

Frequently Asked Questions

The answers below summarise the points on deviations in materials, equipment, practices, test methods and specifications described above.

References

• 21 CFR 211.100, US Code of Federal Regulations (eCFR)
• Schedule M, CDSCO, Drugs Rules, 1945
• EU GMP, European Commission, EudraLex Volume 4
• WHO GMP, World Health Organization
• Indian Pharmacopoeia, Indian Pharmacopoeia Commission
• British Pharmacopoeia, British Pharmacopoeia Commission
• USP, United States Pharmacopeia (USP–NF)