Quality Control, Sampling, and Laboratory Controls
This domain tests the laboratory side of cGMP: specifications and test methods, sampling, out-of-specification investigation, stability programmes, reserve samples and method validation. Most questions are decided by what you may and may not do after an unexpected result.
Laboratory controls
- 211.160 requires specifications, standards, sampling plans, test procedures and instruments, with calibration of instruments, and control of standard solutions, reagents and cultures.
- 211.165 requires each batch to be tested for conformance to final specifications, including identity and strength of each active ingredient, using methods that are accurate, sensitive, specific and reproducible.
- 211.166 requires a written stability programme with sample size, test intervals, storage conditions and number of batches per product per year. 211.170 requires reserve samples of at least twice the quantity needed for all tests except sterility and pyrogens, kept for one year after expiry.
- 211.176 covers penicillin contamination testing. 211.167 covers special testing for controlled-release, sterility and preservative content where applicable.
Sampling
- A sampling plan defines sample size, acceptance number and statistical or empirical rationale. The sample must be representative; sampling error is a frequent root cause of out-of-specification results.
- Sampling of sterile or hazardous materials requires controlled environments, validated tools and trained personnel.
Out-of-specification investigation
- Phase I is a laboratory investigation of analyst error, instrument performance, method execution, calculations and sample handling before any retest.
- Phase II extends to manufacturing, raw materials, methods and equipment. Retesting is permitted only under a written, approved plan with a predefined number of retests, and every result must be evaluated. Retesting until a passing result appears is never acceptable.
- An original result may be invalidated only when an assignable cause is documented. Averaging a failing and a passing result, or reporting a result below the limit of quantification as zero, is prohibited.
Method validation and stability
- ICH Q2 expects specificity, linearity, range, accuracy, precision, detection and quantitation limits and robustness to be established as applicable.
- ICH Q1A(R2) long-term storage is typically 25 degrees Celsius at 60 percent relative humidity, with accelerated conditions at 40 degrees Celsius and 75 percent relative humidity; methods must be stability-indicating.
Worked example
An assay returns 92.0 percent against a 95.0 to 105.0 percent specification. The analyst checks the standard preparation, integration, dilution volumes and sample handling, and finds a 100 mL flask used where 200 mL was required. That is a documented assignable cause, so the result is invalidated, the error is recorded, and a defined retest plan is executed. If no assignable cause is found, the result stands as an out-of-specification result and the batch is investigated.
Traps that cost marks
- Retesting to obtain a passing result, or averaging failing and passing values.
- Declaring laboratory error without documented evidence.
- Forgetting reserve sample quantities, stability commitments and method validation or transfer.
- Sampling only the most convenient containers or locations.