GMP for Active Substances - What are the fundamental Requirements of the ICH Q7 Guideline? - Part 1

Classification and objective

For manufacturers of active substances, compliance with GMP rules in accordance with ICH Q7 is the central benchmark for the appropriate manufacture of active pharmaceutical ingredients (APIs). The requirements are aimed at ensuring that the active substance is manufactured, tested, stored and supplied in the required quality and purity. The most important requirements for manufacturers of chemically and/or biotechnologically produced active pharmaceutical ingredients are summarised below.

1. What is the scope of ICH Q7 and from what point does GMP compliance apply?

• Scope: The ICH Q7 guideline applies to the manufacture of active substances for medicinal products for human use, regardless of whether they are obtained by chemical synthesis, fermentation/cell culture, extraction or by a combination of these processes.
• Start of the GMP obligation: A central requirement is the definition of the "regulatory starting materials (RSM)". From the point at which the defined RSM enters the process, manufacture must be carried out in accordance with the provisions of ICH Q7.
• Stringency of GMP requirements: As a rule, the final manufacturing steps of the process are subject to more stringent GMP requirements than the early steps of the synthesis. These include, for example, late purification and processing steps.

The manufacturer of the active substance must define the point at which manufacture of the active substance begins and must document the reasons for this. For synthetic processes, this is the point at which the "starting materials for the active substance" are introduced into the process. For other types of processes (e.g. fermentation, extraction, purification, etc.), these reasons must be defined on a case by case basis.

2. What are the requirements for quality management and the quality organisation?

Basic principle: Every manufacturer must establish an effective quality management system that requires the active involvement of senior management and of the responsible production personnel. Responsibility for the quality of the active substances produced lies with all those involved. However, there must be an independent Quality Unit (QU), which performs the tasks of Quality Assurance (QA) and Quality Control (QC).

Responsibilities of the Quality Unit include, for example:

• Release/rejection of starting materials, packaging materials, intermediates and the final active substance
• Approval of specifications, manufacturing instructions and quality relevant SOPs
• Assessment and approval of deviations, CAPAs and changes
• Approval and oversight of validations
• Approval and oversight of contract manufacturers, suppliers and laboratories
• Documentation of deviations:
  All deviations from established procedures must be documented; critical deviations must be investigated, root causes identified and corrective measures defined.
• Internal audits:
  Regular, planned self inspections to verify GMP compliance, with documented results and corrective actions implemented within defined timeframes
• Product Quality Review (PQR): Periodic (usually annual) reviews to verify process consistency, including:
  - Evaluation of critical in process and finished product test results
  - Evaluation of OOS/OOT results, deviations, complaints, returns, recalls
  - Assessment of stability data
  - CAPA management and the need for revalidation

3. What are the requirements for personnel?

• Sufficiently qualified personnel: In adequate numbers, with appropriate education, experience and training
• Clear responsibilities: Tasks and roles of all GMP relevant functions must be defined in writing
• GMP training: Regular, documented training on GMP requirements and on specific tasks. The effectiveness check of trainings must be reviewed periodically.
• Hygiene requirements: Suitable work clothing, rules of conduct (no eating, drinking or smoking in production areas), exclusion of infectious or ill persons from GMP critical activities

4. What requirements apply to buildings, facilities and utilities?

Design objective: Prevention of mix ups and contamination

• Layout: Sufficient space, logical material and personnel flow, defined areas for:
  - Goods receipt, quarantine, sampling
  - Storage of released and rejected materials
  - Manufacture, packaging and labelling
  - Laboratory areas
  - Storage of returned and discarded material
  
• Segregated areas and containment:
  - Dedicated areas for highly active substances and, where applicable, highly toxic or highly potent substances, if no proven cleaning/inactivation is in place
  -  Measures against cross contamination (segregated areas, air handling, material and personnel flows)
  
• Utilities:
  - Steam and gas pipes, compressed air and HVAC systems must be qualified and monitored.
  - Special requirements apply to water systems: the minimum water quality requirement is potable water. More stringent systems may be necessary, e.g. where specific microbiological/endotoxin requirements apply. Water treatment processes must be validated and continuously monitored.
  
• Cleaning/sanitisation and maintenance: Cleaning and maintenance schedules, responsible persons, agents and methods must be defined in writing; pest control and contamination control measures must be in place.

5. How to handle equipment ?

• Suitable design and materials: Product contact surfaces must not adversely affect the quality of the active substance (e.g. corrosion resistance; no undesired interactions).
• Qualification: Key production and utility equipment must be qualified (DQ, IQ, OQ, PQ).
• Cleaning and maintenance:
  - Written, detailed cleaning instructions (responsibilities, methods, cleaning agents, disassembly/reassembly, cleanliness checks, permitted hold times)
  - Cleaning validation for multi purpose equipment and in the case of high product criticality
  - Documented evidence that no unacceptable residues or cross contamination occur.
• Calibration: Measuring and control equipment must be calibrated at defined intervals; calibration status must be documented.
• Computerised systems: For GxP relevant systems the following applies: validated use, data integrity, controlled access, back up and archiving.

6. What rules apply to documentation?

Objective: Complete traceability and reproducibility

Main documents:

• Specifications for starting materials, intermediates, final active substance and packaging materials
• Master Production Instructions: Complete, approved instructions for each product/process
• Batch Production Records (batch documentation):
  - Batch specific recording of all critical parameters, excipients, process steps, in process controls, yields, deviations
  - Complete, contemporaneous entries by the executing personnel
• Cleaning and usage logs for equipment
• Laboratory records: Raw data, test reports, calculations, chromatograms, etc.

Important: Changes to documented procedures may only be made through a formal change control system. All documents must be controlled and kept in up to date versions.

7. What requirements apply to the flow of materials?

• Supplier qualification: Suppliers of critical starting materials and active substance starting materials must be assessed and (re)qualified.
• Goods receipt: Identification, quarantine, sampling according to defined plans and testing against specifications must take place here.
• Release/blocking: Labelling of material status (e.g. quarantine, released, blocked, returned)
• Storage conditions: Storage conditions (temperature, humidity, light) must comply with the specifications. Rejected or hazardous materials must be stored under controlled conditions.
• Expiry dates (retest dates): Retest dates must be defined and monitored for starting materials and active substances.

This article will be continued shortly with Part 2.

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)".