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Pharmaceutical CMO Selection & Qualification

This comprehensive Standard Operating Procedure (SOP) is used to select and qualify Contract Manufacturing Organizations (CMOs) in the pharmaceutical industry. It also includes guidelines for establishing Quality Technical Agreements with CMOs to ensure compliance with regulatory requirements and quality standards. This SOP provides a systematic approach to CMO selection, evaluation, and ongoing quality management, helping pharmaceutical companies maintain high product quality standards and regulatory compliance.

Contract Manufacturing Organizations (Pharmaceutical CMO)

1.0   Purpose

    • The Purpose of this SOP is to provide procedures for the qualification and monitoring of Contract manufacturing organizations and Loan License Drug manufacturing facilities.

2.0   Scope

    • This SOP is applicable for Identification & Selection, Conducting Quality Audit/s, Approval/Rejection and Evaluation of Supply of products, Schedule Re-Qualification etc. all of Contract Manufacturing Organizations (CMO).

3.0   Responsibilities 

    • Material Planning Department shall be responsible for;

    • Identification, selection of pharmaceutical CMO and coordinating for relevant document/s from the CMO.
    • Coordinating and helping the Corporate Quality (CQ) department in planning of Quality Audits as per schedule for the respective CMO.
    • Communicating audit plan, Audit agenda, and confirming date/s of audit from pharmaceutical CMO.
    • Communicating Audit reports, Comments on compliance report and conclusion (Approval/Rejection) of Audit with respective CMO.
    • Preparation and maintaining of separate list of Loan license and Third party CMOs along with product manufactured at respective CMO sites.
    • Creating Codes in SAP system along with details like name and address of CMO site (if any).
    • Communicating market complaints with respective CMO and obtaining reports for same.
    • Preparing a list of Contract manufacturing sites.

    • Corporate Quality (CQ) department shall be responsible for;

    • Preparation of Audit Schedule as per frequency and share with planning department.
    • Plan and conduct Quality audit of CMO sites in coordination with the Planning Department and Audit Team.
    • Sharing of the Quality audit report, obtain compliance plan / report for the observations in audit report and follow‑ up for the CAPA, if required in co-ordination with Planning Department.
    • Initiate, review and approve Quality Technical Agreements of pharmaceutical CMO.
    • Evaluating and maintaining all documents of Quality Audits & re-qualification audits and Quality Technical Agreements.
    • Ongoing monitoring and evaluation of CMO and providing recommendations for pharmaceutical CMO sites.
    • Proposing needs a base Audit.

    • Lead auditor and Audit Team shall jointly be responsible for;

    • Conducting audit of CMO sites as per schedule.
    • Sharing Audit agenda, audit observation report to respective CMO sites.
    • Review of compliance report provided against audit observations.
    • Recommending Approval/Rejection of respective CMO site.

    • Designee/ Head QA of CMO shall be responsible for;

    • Readiness of Audit as per the communication of schedule/plan of Quality Audit.
    • Receiving audit observation report and providing compliance report against the observations.

4.0   Procedure for Pharmaceutical CMOs Management

    • General Procedure for Pharmaceutical CMOs

    • Production under contract manufacturing and any other activity covered by good manufacturing practices must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product, or work or analysis, of unsatisfactory quality. Thus, Contract Manufacturing Management is a part of total quality management system that assures that products manufactured from a Contract Manufacturing organization (CMO) are manufactured, packaged, and shipped under a controlled process that results in consistent conformance to quality as per Contract Giver firm quality system.

    • The pharmaceutical CMO Qualification program shall be handled as per below,

    • Identification and selection of CMO.
    • Quality Assessment through Document Evaluation
    • Conducting Initial Quality Audit: Approval/rejection of CMO
    • Quality technical agreement with CMO
    • Ongoing monitoring and evaluation
    • Re-auditing

  • Identification and Selection of pharmaceutical CMO:

    • Planning Department shall identify new CMO.
    • Criteria to identify new CMO shall be based on it’s ability to meet Quality, Regulatory, Operational, Planning Department and Commercial requirements, such as (but not limited to) ;
      • Ability to meet the specification requirements as per Contract Giver firm.
      • Capability to comply with Pharmacopoeia /cGMP requirements & deliver consistent quality products, based on assessment.
      • Ability to supply COA, Shelf life deceleration or stability data /Residual certification and impurity of the materials to be supplied.
      • Should have desired / required Regulatory approval for the marketed Product.
    • Planning Department to confirm the ability of pharmaceutical CMO to meet the demand of Contract Giver firm’s requirements with respect to required volume and timely deliveries.
    • These identified pharmaceutical CMO are further short listed/ selected by Planning Department which has the above criteria.

  • Quality Assessment through Documentation Evaluation

    • Upon receipt of communication on CMO, CQ shall initiate Qualification of CMO by through document evaluation.
    • Following Documents shall be asked from CMO (but not limited to)
    • Manufacturing license issued by applicable regulatory authority
    • List of Product and Product Permission
    • Certificate /Accreditations from various agencies like WHO GMP certificate, ISO certification, US FDA, MHRA, TGA approval etc.
    • Organogram
    • Per annum capacity of manufacturing of product.
    • List of SOPs QA, QC, Production
    • List of Equipments
    • List of Technical Persons
    • CQ shall get these documents from CMO through Planning Department and shallverify for completeness, adequacy and accuracy.

  • Conducting Initial Quality Audit of CMOs:

    • This section covers how audits will be conducted at pharmaceutical CMO manufacturing sites Corporate Quality shall organize the following audits.
    • These audits are conducted as part of Qualification of CMO.
    • These audits shall be completed before commercialization of product.
    • Planning and Conduct of Audit:
    • Corporate Quality shall arrange these audits in co-ordination with Planning Department.
    • Corporate Quality shall form audit team and shall make sure that audit is conducted by a qualified SME & auditor; Resources from Corporate, manufacturing Site QA, Site QC & R&D may be utilized.

    • Qualified Auditor

    • Identify the Person/employee of Contract Giver firm having adequate knowledge, training and experience to carry out activity or process i.e. material (handling /testing), facilities (like raw materials manufacturing facility), auditing skills etc.
    • Head CQ shall evaluate the theoretical and practical knowledge of such identified persons by interviewing identified person.
    • After satisfactory evaluation, the person shall be certified as qualified auditor.
    • Certification of auditor shall be documented as per Format No. – 01.
    • Details of Qualified Auditor covering previous experience details and Job description of the auditor are obtained by Corporate Quality and kept for records.
    • Note: Contract Giver firm may deploy external organization/person for conducting the audit if such organization meets the requirements as mentioned above.

  • CMO Audit Procedure

    • Audit approach is to find the objective evidences. Auditor is expected to cover Quality Management System, adequacy of facility, suitability of equipment/ instruments, competency of the personnel, status of validated procedure etc.
    • Objective of the audit is to confirm compliance of the site to relevant Good Manufacturing Practice and Good Distribution Practices.
    • Audits should be of an appropriate duration and adequate man hours to be employed (based on scope and complexity of audit) and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site.
    • It is recommended to audit all the processes covered in the manufacturing.

    • The following could be some essential processes, but not limited to;

    • Receipt, verification, storage of materials.
    • Stages involved (Extraction, Homogenization, filtering, drying, milling etc.) in manufacturing of substance. Key process parameters of each stage for the suitability and how process is controlled.
    • Specification/ Acceptance Criteria at each stage are met before proceeding to next stage.
    • Bulk packing of finished drug substance, Storage and dispatch etc.
    • Review of any activity that is subcontracted.
    • Refer and review regulatory audit reports for similar observations in data/ process related to the material supplied to the Contract Giver firm.
    • In the beginning of the audit, Auditor(s) shall arrange Opening Meeting to share audit agenda, expectation of the audit and request for documents, if required in advance.

    • Opening meeting may include the following, but not limited to:

    • Introduction/roles/attendance.
    • Objective/scope/criteria.
    • Audit progress.
    • Interim/Closing meetings.
    • Reporting methods including nonconformities.
    • Restrictions/questions.
    • During audit, issues related to regulatory findings shall be verified for the materials purchased by the Contract Giver firm.
    • Compliance to the observations by the pharmaceutical CMO shall also be verified.
    • During audit, the audit team shall review the previous Contract Giver firm’s audit observations and their compliance, if applicable.
    • At the end of the audit, auditor(s) shall arrange Closing Meeting to share the observations.

    • The following shall be considered during closing meeting.

    • Hold the closing meeting to present audit findings.
    • Cover situations encountered during audit that may decrease reliance on audit conclusions.
    • Discuss and resolve diverging audit findings and conclusions.
    • Keep a record if not resolved.
    • Provide recommendations for improvement where specified by audit objectives.
    • Keep minutes and attendance records.
    • Auditor shall collate the information from users of the materials on the issues with pharmaceutical CMO and/or materials received e.g. Rejections, OOS, Complaints pertaining to materials being used and if required these aspects shall be covered in audit.

    • Also shall refer previous audit observations for verifying compliance.

    • At the end of audit, auditor shall brief the observations to the auditee team and discuss, if any disagreement with the observations.
    • If any critical observation is identified, request shall be made for early closure of CAPA.
    • Audit report shall be as detailed as possible and shall reflect what was done and seen in the audit with any discrepancy clearly identified.
    • The audit report shall be prepared as per Format No.: 02 and uniquely identified as;
    • CMO/AR/RR
    • “CMOR” is Contract Manufacturing Organization.
    • “AR” is Audit Report.
    • “RR” is the serial number allotted to the report starting from 01.

    • Audit observations shall be classified as follows, Critical, Major and Minor based on their impact on Quality (but not limited to):

    • Critical: Any observation, which can affect the SISPQ of the product, which may pose serious health risk to the end user.
    • Major: Any observation from the validated and or established process, systems and practices which individually or if put together may affect SISPQ of the product, but does not affect health of the end user.
    • Minor: Any observation which is departure from standard operating procedure or specification or current good manufacturing practices (cGMP) violation, which will not affect SISPQ (Safety, Identity, Strength, Purity and Quality) of the product
    • CMO shall be asked to send compliance plan in about 30 days from the date of receipt of report.
    • In case of critical observation for they shall be requested to send the compliance report within 15 days.
    • If required, on receipt of compliance report Auditor shall re-visit the site at the earliest date and check the execution and effectiveness of CAPA.
    • The contract Giver firm shall not procure any product till the site is re-visited and CAPA execution checked by the AUDITOR.

    • Corporate Quality shall inform Planning department for critical observation, if any.

    • After the receipt of compliance plan, it shall be reviewed by the auditor for adequacy and suitability and communicate to the pharmaceutical CMO by Auditors through Planning Department and Corporate Quality, if any deficiencies observed.
    • Audit shall be closed only after ensuring proper CAPA implemented as per Format No.: 04, “CMO Audit Closure Form”.
    • Based on the Audit observation and compliance received, CQ shall intimate to Planning department about audit conclusion as per format No.: 05, “Audit Conclusion Intimation Form”.
    • Planning department shall prepare update the list of the approved CMO for the Contract Giver firm separately as per format 06 and 07, respectively.

  • Quality Technical agreement with pharmaceutical CMO :

    • Quality Technical Agreement shall be in place between the Contract Giver firm and the approved CMO. Agreement shall be done as per SOP.
    • The Head CQ/Designee shall initiate a Quality Agreement with the approved CMO through the Planning Department. Terms and conditions may be discussed between the Contract Giver firm and the CMO.
    • In case of any changes in the Manufacturing Process or regulatory issues, the CMO shall inform in writing to Planning department and the same shall be intimated to the Head CQ by the planning department.

    • Ongoing Monitoring and Evaluation of CMOs:

    • Ongoing Monitoring:
    • After the approval of the new pharmaceutical CMO, ongoing monitoring and a periodic evaluation shall be performed.
    • For ongoing monitoring and evaluation, different elements shall be considered.
    • The following procedure will define the activities for the ongoing evaluation and finally define the status of the qualification.
    • The evaluation shall be under the control of the Quality Unit but completed as part of a multi-disciplinary team evaluating all aspects of supply.

    • Evaluation:

    • Each pharmaceutical CMO shall be assessed according to the following criteria.
    • Number of complaints reported for product/s supplied
    • Repetitive complaints for the batch
    • Critical or Major observations (if any) by regulatory authorities.
    • The rating system indicates performance and satisfaction. After the periodic evaluation of pharmaceutical CMO shall be classified according to the following rating system.
    • The following categories are examples of a rating system.
    • Completely Satisfactory: Continue supply.
    • Mainly Satisfactory: For Ongoing supply
    • Partially Satisfactory: No supplies until corrective actions are in place.
    • Not Satisfactory: Disqualified
    • The result of the rating has an important impact on the frequency of re-audits, and re-evaluation.

    • Re-Auditing:

    • The frequency of re-audit shall be 3 years from the date of the last audit.
    • Periodic requalification of CMO shall be done as per the Audit procedure explained above.
    • Need-based Audits: These audits are conducted in the following cases, but not limited to;
    • To investigate market complaints received at Contract Giver firm due to material supplied by CMO.
    • In case of serious regulatory findings, the “For Cause Audit” shall be performed within 30 days from the date of receipt of audit observations.
    • Verification of compliance to CAPA proposed by pharmaceutical CMO audit observations given by Contract Giver firm.
    • If the pharmaceutical CMO site has received a warning letter/ import alert from regulatory agencies. The audit shall be planned as part of risk mitigation activity, to verify impact on related data/ product etc.
    • These audits shall be identified as FOR CAUSE audits with specific scope and objective.

    • Dis–qualification / Dis–continuation of CMO

    • Any approved pharmaceutical CMO can be disqualified either temporarily or permanently.
    • Conditions that may lead to temporary disqualification, are but are not limited to;
    • For implementing any critical/major change having an impact on product quality or regulations (facility, manufacturing process, MOC of container closure and shelf life of API, labeling information) without prior approval from the Contract Giver firm.
    • Inconsistent quality rejection of 3 product batches in alternate supplies in a year.
    • Serious regulatory issues from regulatory agencies.
    • CMO is to be kept under temporary disqualification status, till adequate impact/risk assessment is carried out.
    • The decision to continue or disqualify permanently shall be based on assessment and Justification/CAPA provided by the pharmaceutical CMO.

    • Conditions that may lead to Permanent disqualification are but not limited to;

    • Inconsistent quality (rejection of consecutive three batches received at Contract Giver firm).
    • Critical audit findings (which are product quality impacting) observed during the audit by the Contract Giver firm.
    • Sterility failures were confirmed due to material, obvious physical contamination of material with foreign matter at source, Unlabeled Containers, and Contract Giver firm’s critical product complaint due to input material quality.
    • Rejection of pharmaceutical CMO manufacturing Site by Regulatory agencies such as WHO-GMP, MHRA, USFDA, etc.
    • The Corporate Quality Head shall take a call on disqualification within 15 days from the date if any observation/ communication is noticed/ received from any site.
    • The corporate Quality Head/Designee shall issue a written communication to the respective CMO with proper justification. Names of all such pharmaceutical CMOs shall be deleted from the system and approved list of CMOs.
    • The CMOs, who are disqualified temporarily, shall be incorporated in the Approved CMO List, only after the CMO meets the qualification criteria outlined. It shall be done in consultation with the Head of Corporate Quality.

5.0   Attachments and Formates

    • Certificate of an Auditor (Format – 1)
    • CMO Audit Attendance  (Format – 2)
    • Audit Report Format  (Format – 3)
    • CMO Audit Report Log (Format – 4)
    • CMO Audit Closure Form (Format – 5)
    • Audit Conclusion Intimation Form  (Format – 6)
    • List Approved CMO for Contract Giver firm (Format – 7)

6.0   References

    • Revised Schedule M
    • ICH-Q10: Pharmaceutical Quality System

7.0   Abbreviations

cGMP : Current Good Manufacturing Practice
COA : Certificate of Analysis
CAPA : Corrective and Preventive Action
CQ : Corporate Quality
ICH : International Conference of Harmonisation
ISO : International Organization for Standardization
NA : Not Applicable
QA : Quality Assurance
QMS : Quality Management System
SOP : Standard Operating Procedure

 

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pharmabeginers

Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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