GMP for Active Substances - What are the fundamental Requirements of the ICH Q7 Guideline? - Part 2

The following Part 2 of the above-mentioned question complements and completes the preceding Part 1.

8. What must be observed in manufacture, in-process controls and contamination control?

• Manufacture in accordance with master batch records: All critical process parameters and in-process controls are to be defined, documented and complied with.
• In-process controls:
  o Critical control points and tests (e.g. pH, temperature, reaction progress, assay, purity) must be defined.
  o Acceptance criteria must be defined and justified.
• Time limits: Where relevant, process time limits must be defined for critical steps (e.g. maximum interim storage time for moist intermediates).
• Contamination and cross-contamination:
  o Appropriate technical and organisational measures must be implemented (closed systems, dedicated equipment, cleaning, spatial/temporal separation).
  o Handling of flammable, toxic or biologically active substances must be safe and in compliance with GMP.
• Batch Blending: This is only permitted where there is documented justification, control of homogeneity, compliance with specifications and complete traceability.

9. What are the GMP-compliant rules for packaging, labelling, storage and distribution?

• Packaging materials: These must be suitable and qualified to protect the API from moisture, light, oxygen, contamination and mechanical influences.
• Labelling: Clear, unambiguous and error-free labelling is required, including product name, batch number, net content, storage conditions, retest/expiry date and, where applicable, quality grade.
• Label control: Issue, reconciliation and destruction of labels must be controlled, documented and safeguarded against mix-ups.
• Storage: APIs must be stored after release under documented conditions; storage areas must clearly indicate status (e.g. quarantine, released, rejected).
• Distribution:
  o For shipment, it must be ensured that product quality is maintained until arrival at the customer.
  o Traceability (which customer has received which batch) must likewise be ensured.

10. How are laboratory testing and stability/shelf-life testing to be carried out in compliance with GMP?

• Laboratory organisation: Adequate resources, validated test methods and qualified personnel are required.
• Specifications and testing: These must be in place for intermediates (where appropriate) and APIs, including identity, purity, assay, relevant impurities and physical properties (e.g. particle size distribution).
• Validation of analytical methods: All critical test methods must be validated (accuracy, precision, specificity, limit of detection, robustness, etc.).
• Certificates: For each released batch, a Certificate of Analysis (CoA) must be issued, including the relevant tests and results.
• Stability programme:
  o Programme-based stability studies to establish and confirm retest/expiry dates and storage conditions.
  o Ongoing stability studies for representative batches.
• Retention samples: Retention samples for each batch must be stored in sufficient quantity under defined conditions in order to enable subsequent investigations.

11. What GMP principles apply to validation, change control and the handling of deviations?

• Validation policy: This defines which processes, methods, cleaning procedures and computerised systems must be validated.#
• Process validation:
  o Prospective, concurrent or retrospective process validation is possible, but only with a robust data basis.
  o Demonstration that the process reproducibly delivers the API within the defined specification.#
• Cleaning validation: Critical in multi-product facilities or for toxic/highly active APIs.
• Periodic revalidation: Validated systems must be reviewed at defined intervals and in the event of changes.
• Change control:
  o Any potentially quality-relevant change to products, processes, equipment, utilities, specifications or documents is subject to a formal change control process.
  o The impact of changes must be assessed and, where applicable, revalidation and adaptation of regulatory submissions via a directed variation process are required.
• Deviation management & CAPA: Deviation management serves to record, assess, investigate root causes and process deviations. Corrective and preventive actions (CAPAs) are derived from this and must be followed up.

12. What rules apply to the handling of complaints, recalls and returns?

• Complaint handling:
  o All quality-related complaints must be recorded, investigated and assessed.
  o Traceability to affected batches must be established; where appropriate, a risk assessment and information to customers/authorities are required.
• Recall system: Documented procedures must be in place to recall products from the market quickly and effectively; responsibilities and communication channels must be defined.

13. What must be observed with regard to contract manufacturers, traders and special manufacturing processes?

• Contract manufacturers/contract laboratories:
  o Technical evaluation and qualification must be carried out by means of audits; responsibilities, data access and GMP obligations must be regulated contractually.
• Traders/brokers/repackagers: Constant product quality must be ensured through traceability and control of repackaging/re-labelling activities.
• Biotechnological APIs (fermentation/cell culture): Additional requirements apply, including cell bank management, control of culture conditions and virus removal/inactivation.
• APIs for clinical trial materials: In principle, GMP compliance applies here as well, although with certain simplifications regarding changes to the manufacturing process and the controls or tests performed.

Conclusion

For API manufacturers, GMP-compliant manufacture in accordance with ICH Q7 in particular means:

• a robust quality system with an independent quality unit
• suitable and qualified facilities, utilities and buildings
• fully documented, validated and controlled manufacture starting from the defined API starting material
• systematic material and supplier control
• comprehensive laboratory and stability programmes
• as well as strict change, deviation and complaint management

Implementing these core elements creates the basis for regulatory-compliant, safe manufacture of APIs of consistently high quality and, at the same time, for good preparedness for inspections by authorities and customer audits.

You can read the full requirements in the "ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7 (Current Step 4 version dated 10 November 2000)".