ICH Q7 clause 16: Contract manufacturers (including laboratories)
The 7 audit questions covering clause 16, each with the objective evidence to request, the nonconformities most often raised against it and what to sample. Part of the free ICH Q7 API GMP audit checklist, which holds 350 items across 18 clauses.
All 7 questions for clause 16
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§16 Contract manufacturers (including laboratories)
16.10 Are contract manufacturers (and laboratories) evaluated for GMP compliance before use?
- Contract manufacturer audit reports
- Capability assessments
- GMP compliance reviews
- Experience and qualifications verification
- Regulatory history review
- Facility and equipment suitability assessment
- Approved contract manufacturer list
- Periodic re-qualification
- Contract manufacturers used without audit
- No evaluation of GMP compliance
- Inappropriate facilities for product type
- No periodic re-qualification
- Regulatory history not reviewed
- Contract manufacturer re-qualification audits deferred without documented risk-based justification
Contract manufacturers are an extension of the contract giver's operations from a quality perspective. They must comply with the same GMP standards. The contract giver retains ultimate responsibility for quality. Evaluation before engagement typically includes: facility audit, review of quality systems, assessment of relevant experience, review of regulatory compliance history, and verification of capability to meet specific product requirements.
16.11 Is there a written, approved contract (quality agreement) defining the work and quality responsibilities?
- Written quality agreements for all contract arrangements
- QA approval of quality agreements
- Responsibility matrices within agreements
- Communication requirements specified
- Audit rights clauses
- Deviation handling procedures in agreements
- Change control notification requirements
- Periodic agreement reviews
- Contract work without written quality agreement
- Agreements covering only commercial terms
- Responsibilities unclear or overlapping
- No QA approval of agreements
- Agreements outdated and not reflecting current operations
- Quality agreement does not address intellectual property protections for proprietary processes
- Annual Product Quality Review responsibility not assigned to either party in the quality agreement
- Contract manufacturer restricted audit scope to exclude specific production or testing areas
Written contracts (also called Quality Agreements or QAs) are mandatory. Scope must include: specific activities (which steps, which products), quality responsibilities (who does what), communication requirements (notifications, reporting), audit rights, deviation handling, change control, sub-contracting restrictions, regulatory responsibilities. The contract must be approved by the quality units of both parties. Commercial contracts typically separate from quality agreements.
16.12 Does the contract clearly allocate GMP responsibilities between the parties?
- Detailed responsibility matrices
- Specification responsibility defined
- Batch review and approval responsibility
- Stability testing responsibility
- Complaint handling responsibility
- Change control responsibility
- Periodic review of responsibility clarity
- Dispute resolution procedures
- Responsibilities overlap or have gaps
- Specifications prepared by wrong party
- Batch records not reviewed
- Complaint handling dropped between parties
- Changes implemented unilaterally
- Annual Product Quality Review responsibility not assigned to either party in the quality agreement
Detailed responsibility allocation prevents gaps. Common areas for confusion: who prepares specifications, who reviews and approves batch records, who maintains stability programs, who handles complaints from customers of the final product, who manages changes. The contract should assign each responsibility to one party clearly. Responsibilities shared between parties need specific coordination procedures.
16.13 Does the contract permit the contract giver to audit the contract manufacturer?
- Audit rights in contracts
- Audit frequency specified
- Audit SOPs
- Audit reports from contract manufacturers
- For-cause audit triggers and procedures
- Audit finding tracking and CAPA
- Audit team qualifications
- Confidentiality agreements
- No audit rights in contracts
- Audit frequency not specified
- Audits infrequent or never performed
- For-cause audits not permitted
- Audit findings not acted upon
- Contract manufacturer restricted audit scope to exclude specific production or testing areas
Audit rights are fundamental to contract manufacturer oversight. Contracts should specify: routine audit frequency (typically annual), audit scope (which activities, which documents), advance notice requirements (typically 2-4 weeks for routine, shorter for cause), access to records and personnel, confidentiality provisions. 'For cause' audits (quality issues, customer complaints) should permit shorter notice. Contract acceptors should facilitate audits rather than obstruct.
16.14 Does the contract prohibit sub-contracting without the contract giver's prior approval?
- Sub-contracting approval procedures
- Sub-contracting prohibition in contracts
- Sub-contractor evaluation records
- Sub-contract approvals documentation
- Sub-contracted activity identification
- Sub-contractor audit records
- Chain of custody through sub-contractors
- Periodic review of sub-contracting arrangements
- Unauthorized sub-contracting
- Contract giver unaware of sub-contractors
- Sub-contractors not qualified
- No approval records for sub-contracting
- Chain of custody broken through sub-contractors
- Contract giver not notified of sub-contractor engagement until after work commenced
Sub-contracting without approval is a common compliance failure. Contract manufacturers may sub-contract for convenience (capacity, specialized equipment) without realizing the contract giver's obligations. The contract giver loses quality oversight over sub-contracted activities. Prior approval ensures the contract giver can evaluate the sub-contractor and extend quality oversight. The approval process should mirror initial contract manufacturer qualification.
16.15 Are manufacturing and laboratory records available at the site where the activity occurs?
- Record location policies
- Contract giver access procedures
- Electronic system access between sites
- Record retention at activity sites
- Periodic record access verification
- Inspector access procedures
- Record retrieval timelines
- Access rights in quality agreements
- Records not available at activity site
- Contract giver unable to access records
- Delayed record retrieval during inspections
- Electronic systems with access restrictions
- Records centralized away from activity site
- Batch records held exclusively at contract giver site with no access provision for regulatory inspectors at activity site
Records at the activity site support regulatory inspections of that site. Inspectors expect to find records at the manufacturing location. Electronic systems with centralized storage are acceptable if the records are accessible at the activity site. Contract givers need access for their own quality oversight and for responding to their own regulatory inspections. Access terms are typically defined in quality agreements.
16.16 Must the contract manufacturer obtain the contract giver's approval for quality-affecting changes before implementation?
- Change notification procedures in contracts
- Change notifications received log
- Contract giver change approval records
- Emergency change procedures
- Pre-implementation approval verification
- Change impact assessments
- Post-implementation verification
- Periodic review of change communication effectiveness
- Changes implemented without notification
- Notifications after implementation
- Contract giver approval not obtained
- Emergency changes without any notification
- Change impact not assessed by contract giver
- Emergency change notification procedure lacks defined maximum response time for contract giver acknowledgement
Contract manufacturers must obtain contract giver approval for quality-affecting changes. This mirrors the change control requirements within an organization but across the contract boundary. Changes requiring notification: equipment modifications, process changes, supplier changes, specification changes, personnel changes at key positions, facility changes. The contract giver assesses impact and approves before implementation. Emergency changes may have expedited procedures but still require documentation.
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