Glossary

Say what the inspector means

The vocabulary of the product quality review, grouped from purpose to parties. Definitions are ours; the source clause is given where one exists.

Purpose and regulation

Product Quality Review (PQR): The periodic, normally annual, documented review of all authorised medicinal products required by EU GMP, conducted to verify process consistency, the appropriateness of specifications, to highlight trends and to identify improvements.EU GMP Chapter 1, 1.10; PIC/S PE 009 1.10
Evaluation of the review (1.11): The second half of the requirement: the manufacturer and, where different, the MAH must evaluate the results of the review, assess whether corrective and preventive action or revalidation is needed, document the reasons, and manage the actions under the pharmaceutical quality system with effectiveness verified at self-inspection.EU GMP Chapter 1, 1.11
API quality review: The ICH Q7 version for active substances, conducted to verify the consistency of the process, with a seven-item content list that is a subset of the EU list.ICH Q7 2.50, 2.51
Consistency of the process: The first objective of the review: whether the process is producing the same result batch after batch, with a stable mean and spread that the specification contains with margin. Demonstrated by trending, not by conformance.EU GMP Chapter 1, 1.10
Appropriateness of specifications: The second objective: whether the starting material and finished product specifications still fit the process and the product. A specification can be inappropriate by being too loose to detect a problem or too tight for a capable process.EU GMP Chapter 1, 1.10
Ongoing process verification (OPV): The Annex 15 requirement to monitor product quality throughout the lifecycle so that a state of control is maintained, with process trends evaluated and statistical tools used where appropriate. Annex 15 5.31 ties it to the PQR, which is its annual checkpoint.EU GMP Annex 15, 5.28 to 5.31; ICH Q10 3.2.1
Management review: Senior management's periodic review of process performance, product quality and the pharmaceutical quality system. Periodic quality reviews are a defined input.ICH Q10 3.2.4, 4.1

Content of the review

The twelve items: The minimum content of the EU review, items (i) to (xii) of paragraph 1.10: starting and packaging materials; critical in-process and finished product results; failed batches; deviations and CAPA effectiveness; changes; variations; stability; returns, complaints and recalls; previous actions; post-marketing commitments; qualification status; contractual arrangements.EU GMP Chapter 1, 1.10(i) to (xii)
Supply chain traceability: Item (i)'s specific requirement to review the traceability of the active substance back to its registered manufacturer, including intermediaries, for the batches used in the period.EU GMP Chapter 1, 1.10(i); Chapter 5, 5.29
Critical in-process control: An in-process measurement defined as critical because it controls a critical quality attribute. The review trends critical controls, so the list of what is critical, and where it is defined, must be stated.EU GMP Chapter 1, 1.10(ii); ICH Q8 (R2)
Out of specification (OOS): A result outside the registered or approved specification. Item (iii) requires all batches that failed specification and their investigations to be reviewed, whatever the final disposition.EU GMP Chapter 1, 1.10(iii); Chapter 6, 6.9
CAPA effectiveness: Whether a corrective or preventive action achieved its purpose, measured by recurrence or by a defined metric after implementation. Item (iv) requires the review to evaluate it, not just list the CAPA.EU GMP Chapter 1, 1.10(iv); ICH Q10 3.2.2
Marketing authorisation variation: A regulatory change to the terms of the marketing authorisation. Item (vi) requires those submitted, granted or refused in the period, including for third-country dossiers, to be reviewed. Data usually sits with the MAH.EU GMP Chapter 1, 1.10(vi)
Adverse stability trend: A stability result moving towards a limit at a rate that would breach it within the shelf life, whether or not it has breached it yet. Item (vii) requires the review to look for it.EU GMP Chapter 1, 1.10(vii)
Post-marketing commitment: An undertaking given to a regulator at authorisation or variation, such as additional stability data or a process study. Item (x) requires their status to be reviewed.EU GMP Chapter 1, 1.10(x)
Qualification status: Whether equipment and utilities (HVAC, water, compressed gases, critical instruments) were in a qualified and calibrated state throughout the period, with periodic requalification performed on time. Item (xi).EU GMP Chapter 1, 1.10(xi); Annex 15

Data and trending

Trend: To an inspector: any pattern in plotted data over time that a defined rule identifies. A shift in the mean, a change in spread, a drift, a run on one side of the centre line, or a result outside the process's demonstrated range.EU GMP Chapter 1, 1.10
Control chart: A plot of results in time order with a centre line and control limits calculated from the process's own variation. For batch release data the individuals and moving range (I-MR) chart is the usual choice.EU GMP Annex 15, 5.30; Chapter 6, 6.9
Control limits: Limits, usually at plus and minus three standard deviations from the mean, describing what the process actually does. Not to be confused with specification limits, which state what is acceptable.
Process capability (Cpk, Ppk): Indices comparing the process spread with the specification width. Cpk uses short-term (within-subgroup or moving range) variation; Ppk uses the overall standard deviation of the period. A common site threshold is 1.33. Meaningful only for a stable process.
Run rules: Defined patterns on a control chart that signal a non-random cause: the Western Electric and Nelson rule sets are the usual references. The procedure should state which rules are applied.
Out of trend (OOT): A result within specification but outside the process's demonstrated range or in breach of a run rule. Handled at the time under an OOT procedure; the review checks that it was and looks for OOTs that were not recognised.EU GMP Chapter 6, 6.9; Chapter 1, 1.10(ii)
Review period: The defined span of time a review covers, normally twelve months, contiguous with the previous review's period. Stated on the report with the data cut-off date.EU GMP Chapter 1, 1.10
Grouping: Reviewing several products in one report by product type where scientifically justified, typically strengths of one product from a common process. Product-specific data must remain visible within the group.EU GMP Chapter 1, 1.11

Conclusions and actions

Evaluation: The step 1.11 requires after the data is gathered: assessing what the results show and whether corrective and preventive action or revalidation is needed. The step most often missing from a review that has all twelve sections.EU GMP Chapter 1, 1.11; ICH Q7 2.51
Revalidation: Re-establishing the validated state after a change or a loss of control. The review raises the question when a critical parameter has shifted or capability has fallen; it records the decision, it does not perform the study.EU GMP Annex 15; Chapter 1, 1.11
PQR action: A corrective, preventive, monitoring or change action arising from the review, with a stated reason, owner, due date and a route into a tracked system (CAPA, change control, OPV plan, supplier management).EU GMP Chapter 1, 1.11
Self-inspection of PQR actions: Paragraph 1.11's requirement that the effectiveness of the procedures for managing PQR actions be verified during self-inspection. Belongs on the self-inspection checklist.EU GMP Chapter 1, 1.11; Chapter 9
Timely: Performed within the deadline the site's procedure sets after the review period ends. The regulation fixes no number; the QP and the MAH must ensure it is met, and any extension must be documented before the due date.EU GMP Chapter 1, 1.11

Parties and contracts

Marketing authorisation holder (MAH): The company holding the product's authorisation. Where the MAH is not the manufacturer, 1.11 makes it jointly responsible for evaluating the review and for the technical agreement that defines who does what.EU GMP Chapter 1, 1.11
Qualified Person (QP): The person who certifies each batch before release in the EU. Together with the MAH, responsible for ensuring the review is performed in a timely manner and is accurate, and for drawing on it in certification.EU GMP Chapter 1, 1.11; Annex 16
Contract giver: The party outsourcing an activity, ultimately responsible for it, required to supply the acceptor with the information it needs and to review and assess the acceptor's records and results, including the PQR.EU GMP Chapter 7, 7.3 to 7.9
Contract acceptor: The party performing the outsourced activity, typically the author of the PQR where it manufactures the product, required to have the competence and premises for the work and not to subcontract without approval.EU GMP Chapter 7, 7.10 to 7.13
Quality (technical) agreement: The written contract defining each party's GMP responsibilities for an outsourced activity. Must define responsibilities for producing the PQR, and item (xii) requires the review to confirm all such agreements are current.EU GMP Chapter 1, 1.11, 1.10(xii); Chapter 7, 7.14 to 7.17
MAH evaluation: The MAH's documented assessment of a manufacturer's PQR: read, agreement or otherwise with the conclusions, adequacy of actions, MAH-held data omitted, and MAH actions arising. A receipt stamp is not one.EU GMP Chapter 1, 1.11; Chapter 7, 7.9