PIC/S GMP Guide Part 2 is the section of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PE 009) dedicated to active pharmaceutical ingredients: it sets out the GMP requirements for manufacturing the APIs used as starting materials for medicinal products. The text mirrors the ICH Q7 guideline and is, for PIC/S participating authorities, the inspection reference for API manufacturers. In this article we look at what Part II is, how it is structured, from which point of the process it applies, and which points inspectors check most often.
What the PIC/S GMP Guide Part 2 is and who it applies to
The PIC/S GMP Guide (document PE 009) is organised in three blocks: Part I, covering medicinal products (finished dosage forms), Part II, covering APIs, and the thematic Annexes. The version currently in force is PE 009-18, effective 24 September 2026: that revision concerned Annex 19 (Reference and Retention Samples), while Part II was not changed.
Part II derives from ICH Q7 "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients", adopted by ICH in November 2000 and transposed essentially verbatim by both PIC/S and the European Union (EudraLex Volume 4, Part II). This alignment is a practical advantage: an API site compliant with Part II is, in effect, working to the same text referenced by PIC/S authorities (including AIFA, Swissmedic, TGA and FDA) and by EU GMP.
It applies to the manufacture of APIs for human use obtained by chemical synthesis, extraction, classical fermentation, cell culture and recovery from natural sources, including repackaging and relabelling sites, brokers and traders. Explicitly excluded from the scope, per ICH Q7, are vaccines, whole cells, whole blood and plasma and their derivatives, and gene therapy APIs; for sterile APIs, sterilisation and aseptic processing steps are not covered by Part II and fall under the requirements for medicinal products (Part I and Annex 1).
Where GMP starts: the API Starting Material
The most important operational concept in Part II is that GMP does not apply from the beginning of the synthesis, but from the point at which the API Starting Material is introduced into the process. The starting material definition must be proposed by the manufacturer and scientifically justified: from that point onwards, requirements increase progressively along the process, up to maximum stringency in the final purification, isolation and packaging steps.
ICH Q7 itself contains an applicability table which, for each type of manufacturing (chemical synthesis, extraction, biotechnology, classical fermentation), indicates the step from which the text becomes binding. During audits, the starting material justification and the consistency between the registration dossier and what actually happens on site are among the first things verified.
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The structure of Part II: 20 chapters
Part II is organised in 20 chapters covering the entire API lifecycle. The table summarises the main blocks and their operational focus.
| Chapters | Topic | Operational focus |
|---|---|---|
| 1–3 | Introduction, Quality Management, Personnel | Scope, quality unit independent from production, training and hygiene |
| 4–5 | Buildings, facilities and equipment | Segregation, utilities, cleaning, calibration and computerised systems |
| 6–7 | Documentation and materials management | Batch records, specifications, sampling and release of materials |
| 8–10 | Production, packaging, storage and distribution | In-process controls, expected yields, labelling, returns and shipments |
| 11–12 | Laboratory controls and validation | API specifications, stability, retest dates, process, cleaning and method validation |
| 13–16 | Change control, rejection and re-use, complaints and recalls, contract activities | Change evaluation, reprocessing vs reworking, solvent recovery, quality agreements |
| 17–19 | Agents, brokers and distributors; cell culture/fermentation; APIs for clinical trials | Supply chain traceability, biotech-specific requirements, proportionate GMP for IMPs |
| 20 | Glossary | Binding definitions (starting material, intermediate, mother liquor, etc.) |
Two chapters deserve special attention. Chapter 14 governs the difference between reprocessing (repeating a step that is part of the established process) and reworking (treatment using different steps, which requires investigation, evaluation and, as a rule, additional data): confusing the two is a classic mistake. Chapter 17 extends GMP obligations to those who do not manufacture but trade, repackage or relabel APIs: even a trader must guarantee full traceability back to the original manufacturer.
Part I vs Part II: what actually changes
Compared with Part I, Part II reflects the chemical and often multi-purpose nature of API plants. The most relevant practical differences: the acceptability of cleaning standards and environmental classification proportionate to the process step (requirements increase towards the final steps); the use of a retest date as an alternative to an expiry date for many APIs; the central role of the starting material definition, which does not exist in Part I; and the handling of mother liquors, solvent recovery and reprocessing, typical of chemical synthesis. The system pillars remain identical: an independent quality unit, change control, deviation management, validation and data integrity.
For European manufacturers the framework is reinforced by the fact that using active substances manufactured in accordance with GMP is a legal obligation for the holder of the manufacturing authorisation for the medicinal product: API supplier qualification and audits at their sites are, in practice, conducted against Part II.
The points most frequently checked in inspections
- Justification of the API Starting Material and consistency with the registration dossier.
- Independence and responsibilities of the quality unit: batch release, approval of specifications, procedures and changes.
- Management of reprocessing, reworking and solvent recovery, with supporting rationales and data.
- Laboratory controls: OOS management, on-going stability, retest date assignment.
- Supply chain traceability for brokers, traders and repackagers (chapter 17).
- Process and cleaning validation in multi-product plants, with defensible carryover limits.
GuideGxP recommendation
Treat Part II as a text to be mapped, not just cited: build a matrix crossing the 20 chapters with your SOPs and with the available evidence (batch records, change control logs, validation reports), and use it both for self-inspections and to prepare audits of your API suppliers. Dedicate a written rationale to the starting material definition and review it at every process or supplier change: it is the point where a PIC/S inspection can challenge the entire GMP perimeter of the site. And remember that ICH Q7 does not live alone: it interacts with ICH Q9 (risk management), Q10 (quality system) and Q11 (development and starting material definition).
To master the entire ICH Q series — including Q7 and its links with Q8–Q12 and the new Q1 — our operational guide Quality Guidelines ICH Q: what really applies, and readiness for the new Q1 states, sentence by sentence, where the ICH text has binding force and how to demonstrate it in audits.
