Fundamentals of Quality Control Practice in Pharmaceuticals

QC testing is only designed to test for product attributes that are well-known and understood. These attributes are part of the product specification. However, laboratory testing cannot pick up all defects because the test may not exist, the test may not be sensitive enough, or the test may not be required for that product.

Companies therefore have to rely upon GMP rules and QA systems to prevent these problems from occurring in the first place.

US FDA CFR 211 

Sec. 211.160 General requirements.

(a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit.

(b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

International GMPs 

Chapter 1: Quality control

1.3. Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been Judged to be satisfactory.

QC is the part of QA that checks the quality of a batch after it has been manufactured. QC verifies that ingredients and products meet written and approved standards, often called “specifications”.

The QC laboratory tests samples of raw materials and finished products. It is critical to get accurate results from QC tests. Otherwise, defective batches may be released and good batches may be rejected.

The role of the QC laboratory then, is to detect any possible defects once they have occurred, rather than prevent them from occurring in the first GMP Rules place. The QC laboratory’s specific responsibilities include: –

  • sampling, inspecting, and testing of starting materials and finished product
  • calculating and checking results against specifications
  • reporting all results and releasing on~ passed batches

Typical sample flow in a QC laboratory

Received Labelled Sample

The laboratory maintains a Sample Receiving Register. This register logs the botch and sample number, number of samples provided and the lime and date the sample first entered the laboratory. This is the commencement of sample tracking.

Prepare samples and set up

Many test methods require sample preparation before the test is run. The test method should describe exactly how the sample is prepared. This may involve simple dilution or more complex extraction and manipulation. Always refer to the current test method before setting up the sample.

Run test sample

Once the sample is prepared, it is included in the test run. Care must be taken to ensure that the sample is not degraded, e.g. by spillage, exposure to atmosphere, or temperature degradation on the bench. Always refer to the current test method for instructions on how to protect the sample during testing. Concurrent with testing the sample, analysts should ensure that the instrument or a logbook records the sample number, and it traced exactly to the test result.

Verify system suitability

For instrumental runs such as HPLC/GC, the test method usually includes a verification that the entire instrumental system is performing satisfactorily on the day of the run. This is called “system suitability testing” (SST). Non-instrumental methods may also include control or equivalent verification systems. The test methods should describe how the integrity of particular test runs is verified.

Calculate/check results

Once the sample has been run, either the instrument or the analyst will perform a calculation to arrive of a result. It is essential to double check all calculations before finalizing sample results.

Out of specifications?

All QC laboratories have written procedures for handling and investigating only result that appears to be OOS. The analyst should ensure that as soon as an OOS event occurs, supervision is notified, the sample is retained, and a documented investigation is commenced. 

Report result

Once the sample has been run, either the instrument or the analyst will perform a calculation to arrive of a result. It is essential to double check all calculations before finalizing sample results.

Current test method

Before commencing any assay, the analyst should refer to the current version of the test method. The test method should be available at the worksite.

Qualified instruments

Samples must be processed through qualified and calibrated instruments. The analyst should be aware of the status of the instrument before conducting the test. In particular, the analyst should pay attention to the instrument calibration status. If an instrument is out of calibration, do not proceed with the test. All laboratory instruments, upon introduction to the laboratory, should undergo formal qualification.

Reference standard

Many tests require comparison of the sample to an official reference standard. The some core should be taken in preparing the reference standard as is taken when preparing the sample for test. The analyst should ensure that only the current approved reference standard should be used. The reference standard number must be recorded in the test record.

Current specification

In all QC testing laboratories, there will be a set al published and approved specifications for each starting material and finished product. When calculating and checking results, the analyst should refer to the current specification to decide the status of the sample. These specifications are often registered with the regulatory agency and cannot be changed.

Role of the laboratory

QC compliance encompasses many activities that are documented in the GMP rules.

Sampling

Sampling of starting materials and finished products is completely governed by GMP regulations. All sampling procedures and plans must be documented.

If wrong or insufficient samples are taken or a poor sampling technique is used, any subsequent testing may then give misleading results. As a result, good product may be rejected, or much worse, defective product may be released.

Testing

Testing of samples in the laboratory is a mandatory requirement under GMP regulations. Its effectiveness, though, is limited because the entire batch cannot be tested nor can the batch be tested for all types of potential contamination.

In fact, QC testing is limited to looking for defects after they have occurred, so it is not a QA prevention system but rather a defect detection system.

Reporting results

Laboratory documentation and records must follow the same rules as manufacturing GMP documents. The QC lab is required to have SOPs, test methods, specifications, registers, logs and testing records in place.

These documents must be current approved, accurate, provide traceability and be archived for later review. Government auditors are particularly interested in the QC testing records when they conduct GMP audits.

Laboratory documentation

Each product has a specific set of specifications registered with the government authorities. Starting materials and finished products are required to be tested to these specifications, and the results reported to QA management if there is a problem.

Batches may not be released to the market if results do not conform to the approved specifications. 

G(Control)LP

GMP rules is they are applied to the QC laboratory are sometimes called G(Control)LP rules, or G(C)LP. These G(C)LP rules are also checked during laboratory audits:

  • Conduct test to approved, written test methods.
  • Calibrate and quality instruments.
  • All samples and standards are traceable and accounted for.
  • Complete test records accurately and in real time.
  • All tests are supported by validated methods.
  • Record or capture all generated raw data directly, promptly and legibly.
  • Use traceable data sheets or sequentially numbered notebooks.
  • Date and sign or initial data entries on the day of entry.
  • Archive records so that they are protected secure, and easily retrievable.

Laboratory documentation

The laboratory documents are designed to ensure there is linkage between the standard procedures and test methods (what is required to do) and the laboratory records (what was actually done).

This forms the laboratory records quality system.

Laboratory quality manual

The laboratory quality manual and laboratory policies are top level documents describing the overall management and organisation of the laboratory. These documents should reflect the requirements under GMP rules.

Standard operating procedures

Standard operating procedures provide more detailed and specific requirements for each of the laboratory quality elements. For example, SOPs describe how to handle a sample, how to conduct an audit, how to release a result from the laboratory and how to manage a complaint. SOPs are generally not specific to test methods.

Test methods and specifications

Test methods provide specific step-wise direction on how to properly execute a test procedure in a standardized manner. A test method is specific to on analysis and for on instrumental technique such as HPLC. Specifications generally accompany test methods and provide pass/fail criteria and acceptance criteria for a test method, such as system suitability or control limits.

Sample and reagent preparation sheet

Sample and reagent preparation sheets are used to document the instructions for preparing laboratory solutions, standards, and working reagents. It is important in a laboratory to provide accurate instructions and records of these preparations. Usually these sheets are linked to specific test methods. Equally important are the instructions for calibrating standard solutions.

Laboratory documents

Records of testing include laboratory analyst note books, specific testing sheets, and analytical printouts, electronic records such as chromatographs, and ancillary records that support the compliance of the laboratory. Ancillary records would include calibration reports, training records, and monitoring of the environment.

Specifications

Specifications are documented for starting materials, in-process product, and finished products. These specifications are submitted to the regulatory authorities when products are first registered. If specifications need to be altered for whatever reason, approval must be sought from the government regulators.

The finished product is required to meet the specifications throughout the full shelf life under the approved storage condition.

Each batch must conform to each specification when tested. All out-of-specification (OOS) conditions must be investigated.

Pharmacopoeias are legal standards for the quality of products and materials. They specify the quality attributes of products and materials in “monographs”, and provide information on how tests should be conducted.

Starting materials

In the pharmaceutical industry, the requirements for starting materials must be well-defined and documented to ensure that you get the material specified or ordered, and that there are no mixups.

Starting materials are defined by a standard name, the supplier’s/ manufacturer’s code, and a unique item code.

Specifications for starting materials should include:

  • inspections and/or tests required
  • reference to test methods and acceptance criteria
  • material storage conditions
  • a retest or expiry date
  • reference to pharmacopoeial method (if available)
  • approved supplier and manufacturer (if available)
  • sampling instruction or reference
  • any precautions

Intermediate products

In the pharmaceutical industry, specifications for intermediate and bulk products should be available if these are received or dispatched, or if data obtained from tests on intermediate or bulk products are used for the evaluation of the finished product or further processing.

The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Packaging materials

In the pharmaceutical industry, the requirements for pre-printed packaging materials must be well-defined and documented to ensure that you get the items you specified or ordered and that there are no mixups.

Packaging materials are defined by a standard name, and a unique item code.

Specifications for packaging materials should include:

  • a detailed description of the item
  • inspections and/or tests required
  • acceptance criteria
  • an approved label copy
  • approved supplier and manufacturer (if available)
  • sampling instruction or reference
  • storage conditions
  • any precautions

Finished products

Specifications for products typically include:

  • an exact statement of the active material
  • the product code (if any)
  • the dosage form and/or strength
  • physical appearance and identity
  • all tests and their limits
  • details of, or reference to, the test methods
  • sampling instructions
  • the shelf life and storage conditions
  • designated name
  • package details
  • formula (or reference to a formula) any precautions

Out of Specification (OOS) conditions

If a single assay result does not meet the agreed specification, a laboratory investigation is required before any repeat assays are conducted.

The laboratory must determine, if possible, whether a laboratory error or a sample or batch failure is the cause of the out-of-specification result.

The Investigation should be documented according to a written procedure.

Test method validation

The laboratory is required to demonstrate that all test methods are reliable, this means they must be validated by verifying the following attributes:

  • precision (amount of variation in the assay)
  • accuracy (difference between the average results and the “true” value)
  • selectivity (ability of the method to measure the analyte in the presence of interfering compounds)
  • sensitivity (limit of quantitation or limit of detection of the method)
  • linearity and range (over what range the method measures the analyte in direct proportion)
  • ruggedness (how the test method Is affected by reasonable changes)

If a method is not validated, it is difficult to be assured that the results are reliable. GMP requires that all critical steps of manufacture are reliable or validated. This naturally includes laboratory test methods.

Sampling

Sampling is the removal of are presentative portion of a lot to access the lot’s composition and characteristics. The purpose of testing samples is to make some inference about the lot from which the sample is drawn:

  • to determine the quality level
  • to detect a certain level of defects
  • to assess the level of heterogeneity
  • to identify mix-ups, mislabelling, or contamination

It is assumed or accepted when sampling that:

  • There is an agreed or implied inherent risk in any conclusions.
  • Defects are randomly distributed in the batch.
  • The production process is stable and continuous.

The sampling game

Imagine that the packaging department receives a container of 500 widgets from the bulk manufacturing department every week for weeks in a row. As part of in-process QC, the laboratory takes 10 samples at random from the bulk pallet and tests them for defects. If the laboratory finds a defect in any one sample, they can either reject the lot or resample another 10.

Play the sampling game to see if sampling and testing can be used to accurately assess the defect levels in the production line.

If one of the numbers drawn matches one of your nominated defective units, the batch will have a defect.

There will be a total of batches sampled.

Sampling limitations

No matter how well or how often QC testing is conducted, there is always some risk that defects were not detected in the lot.

This means that defective product could be released even though it passed all the tests. If one wanted to be 100% sure that a batch does not contain any defects, every unit would have to be tested. Since this is not practical, some risks would have to be accepted.

Despite these limitations, GMP regulations require companies to routinely conduct QC test. However, properly following GMP regulations and QA rules during manufacture and packaging will help prevent defects from occurring in the first place, which reduces the company’s reliance on QC testing.

Sampling plan and risks

Sampling plans decide which lots of product to accept and release, and which lots to reject and either rework or discard. Ideally, a sampling plan should reject all “bad” lots while accepting all “good” lots. However, because the sampling plan bases its decision on a sample of the lot and not the entire lot, there Is always a chance of making an Incorrect decision. This is termed the sampling risk. If a good lot is rejected incorrectly, this is called the suppliers risk. Conversely, if a poor lot Is accepted Incorrectly, this is called the consumers risk. Sampling plans generally try and set these risks between 5% and 10%.

Naturally, the way the sample is selected has a big impact on the level of risk.

Altering records

A critical part of QC is ensuring the reliability of results.

One way to ensure that the results are error-free is to conduct a second check of calculations and raw data. This check should be independent that is, done by a different analyst or supervisor.

  • The following should be checked:
  • The record has been completed to quality control standards.
  • Current approved test method and specifications were used.
  • There was an accurate recording or summary of results from the chromatographs.
  • All calculations are accurate.
  • Replicate results ore internally consistent.
  • There were no deviations from the approved test method.
  • Results reported are within specification.

Observations, data and calculations shall be recorded at the time they are made and shall be identifiable to the specific task.

When mistakes occur in records, each mistake shall be crossed out, not erased, made illegible or deleted, and the correct value entered along side, All such alterations to records shall be signed or Initialed by the person making the correction. In the case of records stored electronically, equivalent measures shall be taken to avoid loss or change of original data.

(extract from ISO 17025)

Pharmaceutical Quality System (PQS) 

ICH Q10 Guidance

The PQS covers the entire lifecycle of a product from development to product discontinuation.

The PQS guidance combines critical management principles and key processes that support product quality throughout the lifecycle of the product.

2.1 Management Commitment

(a) Senior management has the ultimate responsibility to ensure an effective pharmaceutical quality system is in place to achieve the quality objectives, end that role, responsibilities, and authorities are defined. Communicated and implemented throughout the company.

(b)(5) (Management should conduct) management reviews of process performance and product quality and of the pharmaceutical quality system …

3.2.1 Process performance and product quality monitoring

Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state or control is maintained.

An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement.

3.2.2 Corrective Action and Preventive Action (CAPA) System

The pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring…

3.2.3 Change Management System

….The change management system ensures continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance there are no unintended consequences of the change…

(q) Quality risk management should be utilized to evaluate proposed changes…

Management responsibility

The PQS places additional emphasis on the critical role management plays in ensuring product quality, compliance and effective process controls. Management provides leadership, and approves processes, systems and resources. They also take ultimate responsibility for the effectiveness of the QA. GMP and QC processes and procedures.

Change of ownership

When product ownership changes, management should consider the complexity of this and ensure that the ongoing responsibilities are defined for each company involved and that the necessary information is transferred.

Resource management

Management should ensure that resources are appropriately applied to a specific product process or site.

Quality planning

Senior management should ensure the quality objectives needed to implement the quality policy are defined and communicated. Performance indicators that measure progress against quality objectives should be established, monitored, communicated regularly and acted upon.

Product quality reviews

Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained.

Quality policy

Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality.

Management review of the quality system

Management should assess the conclusions of periodic reviews of process performance and product quality and of the PQS.

Management commitment

Senior management has the ultimate responsibility to ensure an effective PQS is in place to achieve the quality objectives, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the company.

Internal communication

Communication processes should ensure the appropriate and timely escalation of certain product quality and PQS issues.

Management of outsourced activities and purchased materials

The pharmaceutical quality system extends to the control and review of any outsourced activities and quality of purchased materials.

Corrective and preventive action (CAPA) systems

Neither the FDA CFR 211 regulations nor international GMP standards specifically mandate CAPA systems as part of the quality assurance system, however, they are implied and expected. ICH Q10 makes this requirement more explicit.

A compliant CAPA system consists of the following:

Quality Policy

While not essential, it is helpful to describe the CAPA system as a policy, since it is such a critical quality system element. This ensures everyone knows actions to fix problems essential to compliance and improvement.

CAPA SOP

The CAPA SOP describes the processes required actions and responsibilities for identifying, processing and resolving CAPA issues.

CAPA Report

The CAPA report describes the actual CAPA event and provides a GMP record of how it was resolved. The CAPA records will also be of interest to government auditors. 

CAPA Register

The register provides a list of CAPA events and their current status. From the register, managers can tell which CAPA events are the most common, and what stage they are at in being resolved. The register will also be of interest to government auditors.

In addition to this documentation, best-practice CAPA systems also have the following features:

  • in-built risk assessment
  • a means to trend CAPA to identify related issues
  • assigned responsibilities for CAPA actions
  • a system for identifying when a CAPA closeout has not been met
  • integration with management review meetings

Corrective Action

The organization shall take action to eliminate the cause of nonconformities in order to prevent recurrence. Corrective actions shall be appropriate to the effects of the nonconformities encountered.

A documented procedure shall be established to define requirements for

  1. reviewing nonconformities ( including customer complaints),
  2. determining the causes of nonconformities,
  3. evaluating the need for action to ensure that nonconformities do not recur,
  4. determining and implementing action needed,
  5. records of the results of any investigation and of the action taken, and
  6. reviewing corrective action taken and its effectiveness.

Source: ISO 13485 extract

Preventive Action

The organization shall determine action to eliminate the causes of potential nonconformities in order to prevent their occurrence. Preventive actions shall be appropriate to the effects of the potential problems.

A documented procedure shall be established to define requirements for

  1. determining potential nonconformities and their causes,
  2. evaluating the need for action to prevent occurrence of nonconformities,
  3. determining and implementing action needed,
  4. records of the results of any investigations and of action taken, and
  5. reviewing preventive action taken and its effectiveness.

Source: ISO 13485 extract

CAPA phases

The CAPA system can be broken down into four distinct phases, each of which requires different actions, different outcomes, and probably different responsibilities.

Initiating event

A potential CAPA can be initialed from multiple different sources or events:

  • External events or marketplace feedback such as complaints, adverse events, or service reports.
  • Manufacturing nonconformities such as errors, process deviations, laboratory out-of-specifications, or starting material failures.
  • Quality management system noncompliance originating from, for example, documented procedures, internal audits, regulatory audits, or product or process trend reviews.
  • Poor product design

CAPAs can also originate from opportunities to improve any of the above.

Raising the CAPA

Not all problems or issues necessarily warrant a CAPA report. Companies should put in place business rules that qualify on issue as a CAPA.

One of the key tools for qualifying a CAPA is risk assessment. Generally applying risk assessment to an issue will answer the question: “Does this incident merit a further investigation and a CAPA?”

If a CAPA is raised, it should be formally documented using a CAPA form and assigned a unique tracking number. Responsibility is then assigned for conducting an investigation and root cause analysis. There are no particular rules regarding who should assume responsibility, but often it is the group or person that knows most about the problem or will derive benefit by its resolution.

The CAPA plan

This phase is about ensuring that there is a clear CAPA action plan based on the investigation and root cause analysis in the previous phase. The plan should be approved, actions to be taken should be set out, responsibilities assigned, and target completion or progress review dates nominated for particularly large CAPAs, a formal project plan would be useful.

The CAPA plan should be approved by the quality representative and the area management before implementation. The plan should also be linked to change controls where they apply.

Implement, monitor and close

The last phase of a CAPA is to implement the approved plan and track is progress against agreed dates.

Once a CAPA plan is implemented, it is necessary to verify that it has been effective by monitoring the Impact of the actions. The verification could be immediate or delayed until the CAPA impact becomes evident. It is usual to keep the CAPA in “open” status during the monitoring phase until it is formally closed.

Summary

Quality is everyone’s job, and it should pervade every aspect of pharmaceutical manufacture and packaging. Quality should not be tested into products, rather, it must be built in at each step or manufacture.

Quality manifests itself in not only obvious ways, such as during actual processing steps, but also in diverse areas such as in vendor assurance, personnel training, internal audits, change management, release for supply, and QC sampling.

Pharmaceutical manufacturers must integrate the key functions of quality control (which checks for defects after they have occurred) and regulations or GMP under the banner of quality assurance. QA is charged with preventing defects and errors from occurring by overseeing all aspects of producing a quality product.

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