SOP for Contract Manufacturing in Pharmaceutical

Standard operating procedure of Contract Manufacturing in the Pharmaceutical Industry.

1.0 目的:

To set out how contract manufacturing work is handled at the site. This covers product made for an outside party and also product that the site has made by an outside party on its own behalf. The goal is to keep product quality, patient safety, and GMP compliance in place throughout the arrangement.

2.0 範囲:

This Procedure covers every contract manufacturing arrangement that the site is party to. It applies whether the site is the Contract Giver or the Contract Acceptor. Clinical trial batches, commercial product, and product for export all fall inside the scope.

3.0 責任:

Contract Manufacturing Officer, QA Manager & Regulatory Affairs Officer

4.0 説明責任:

QA Head & Qualified Person (QP).

5.0 手順:

5.1 Two roles sit at the heart of any contract manufacturing deal. The Contract Giver is the party that owns the product and the marketing authorization. The Contract Acceptor is the party that actually makes the product at its own site.

5.2 Both roles carry clear duties under GMP. The Contract Giver stays responsible for the product as sold, even though someone else made it. The Contract Acceptor has to make that product to the standard spelled out in the agreement.

5.3 Every contract manufacturing arrangement at this site is backed by two separate papers. The commercial contract covers price, volume, and delivery. The Quality Agreement covers every quality related duty of each party.

5.4 No product may be made, shipped, or released under a contract arrangement until both papers have been signed by the QP on each side.

5.5 Vetting a New Contract Partner:

5.5.1 Every new partner has to go through a vetting process before a contract is signed. This applies in both directions, whether the site is giving the work or taking it on.

5.5.2 Vetting covers the following areas:

5.5.2.1 GMP status: a current manufacturing license and, where needed, a valid GMP certificate from the relevant authority.

5.5.2.2 Audit history: any open regulatory findings, recall history, and inspection results from the last three years.

5.5.2.3 Technical capacity: the right equipment, the right trained staff, and enough capacity to meet the planned volume.

5.5.2.4 Quality system: a documented quality management system with change control, deviation, and CAPA all in place.

5.5.2.5 Financial health: a basic financial check to rule out any partner at risk of going under during the contract term.

5.5.3 An on site audit is run before any contract is signed. The audit checks every area listed above through direct observation, document review, and staff interviews.

5.5.4 The Vendor Audit Report goes to the QA Head. Any finding rated major or critical has to be closed before the contract is signed.

5.5.5 A partner that fails the vetting step is turned down. The Vendor Audit Report and the rejection reason are retained on file for future reference.

5.6 Quality Agreement:

5.6.1 The Quality Agreement is the core document that defines how quality is managed across the two sites. It sits alongside the commercial contract but is a separate paper in its own right.

5.6.2 Each Quality Agreement has to cover these points at a minimum:

5.6.2.1 A clear split of duties between the two parties, done either as a table or a responsibility matrix.

5.6.2.2 The product list covered by the agreement, with strengths, pack sizes, and markets.

5.6.2.3 Rules for changes to the product, the process, the site, or the supplier.

5.6.2.4 How deviations, complaints, adverse events, and recalls will be handled by each side.

5.6.2.5 Batch release rules, naming the Qualified Person who signs for final release.

5.6.2.6 Audit rights, including the right of the Contract Giver to audit the Contract Acceptor site at reasonable notice.

5.6.2.7 Sample retention rules: how many samples, what conditions, for how long, and who holds them.

5.6.2.8 Document retention rules: who keeps which records and for how long.

5.6.3 The Quality Agreement is reviewed by QA on both sides every two years at a minimum. A review can also be triggered by any major change or any regulatory action.

5.6.4 All changes to the Quality Agreement run through the Change Control system. Both parties must sign off before a change takes effect.

5.7 Technology Transfer:

5.7.1 Before any batch is made, the product has to be transferred from the Contract Giver to the Contract Acceptor. This is called technology transfer.

5.7.2 The Contract Giver hands over the following documents as part of the transfer:

5.7.2.1 Master Batch Manufacturing Record.

5.7.2.2 Master Batch Packing Record.

5.7.2.3 Product specifications and analytical test methods.

5.7.2.4 Stability data for the product.

5.7.2.5 Process validation reports from the original site.

5.7.2.6 Regulatory filings in the markets where the product is sold.

5.7.3 The Contract Acceptor sets up a local Technology Transfer Protocol. The protocol lists every step needed to bring the product online at the new site.

5.7.4 A set of engineering batches is made first. These batches are used to prove the process works on the Contract Acceptor’s equipment without fault.

5.7.5 After the engineering batches, three consecutive validation batches are made at full commercial scale. Each batch goes through a full set of tests for identity, assay, dissolution, and related substances.

5.7.6 A Technology Transfer Report closes out the transfer. The report states that the product meets all specs at the new site and is ready for commercial manufacture.

5.8 Material Supply:

5.8.1 The Quality Agreement names who supplies each raw material, packaging material, and active ingredient. In most arrangements, the Contract Giver supplies the active ingredient and the Contract Acceptor sources the rest.

5.8.2 Any supplier of active ingredient has to be approved by the Contract Giver. The Contract Acceptor cannot switch the active ingredient supplier without a formal change request.

5.8.3 Materials supplied by the Contract Giver come with a certificate of analysis for each batch. The Contract Acceptor does identity testing on receipt but does not repeat the full release testing.

5.8.4 Materials sourced by the Contract Acceptor follow the full incoming goods SOP. A certificate of analysis is filed for every lot.

5.8.5 A material shortage is flagged between the two parties within 24 hours. No batch is started with insufficient material to finish.

5.9 Batch Manufacture and Oversight:

5.9.1 Each batch is made to the Master Batch Manufacturing Record that came across during technology transfer. The Contract Acceptor cannot change the record without written approval from the Contract Giver.

5.9.2 A Person in Plant (PIP) may be posted by the Contract Giver during production. The PIP watches the batch being made and signs off on key steps.

5.9.3 In process quality checks run as listed in the master record. Any out of spec result is logged as a deviation and reported to the Contract Giver within one working day.

5.9.4 Batch documents are reviewed by QA at the Contract Acceptor first. A full copy of the signed batch record then goes to QA at the Contract Giver.

5.9.5 Samples are drawn from every batch for quality control testing and for retention. The sample plan is set in the Quality Agreement.

5.10 Batch Release:

5.10.1 Batch release can be a single step or a two step process, depending on the market.

5.10.2 For a single step release, the Qualified Person at the Contract Acceptor releases the batch based on the signed batch record and all test results. This model is common for straightforward toll manufacture.

5.10.3 For a two step release, the Contract Acceptor does a technical release and the Contract Giver does a marketing release. Both signatures are required before the product can be shipped to any market.

5.10.4 No batch is released if any test falls outside the approved specification. An out of spec result opens an investigation per the site deviation SOP.

5.10.5 The Qualified Person keeps a signed Release Decision Log. Every batch release, hold, and reject decision goes into this log with the date and the reason.

5.11 Change Control:

5.11.1 Any change that affects product quality at either site has to go through the Change Control system. This includes changes to formulation, process, equipment, facilities, specifications, and suppliers.

5.11.2 The party proposing a change raises a Change Control Request and sends it to the other party for review. The other party has 30 days to respond with approval, rejection, or a request for more information.

5.11.3 A change is not put into practice until both parties have signed off on it. Silent approval does not apply to contract manufacturing work.

5.11.4 Regulatory filings for changes are handled by the party named in the Quality Agreement. In most cases this is the Contract Giver as the marketing authorization holder.

5.11.5 Emergency changes can be put in place before written approval, but only with a verbal approval from the QA contact at the other party. The verbal approval is followed up with written confirmation within 48 hours.

5.12 Deviations and Complaints:

5.12.1 A deviation at the Contract Acceptor site is reported to the Contract Giver within one working day. The report covers what happened, what product is affected, and what action has been taken.

5.12.2 A deviation investigation is run jointly. The Contract Acceptor leads the technical investigation. The Contract Giver reviews and approves the findings and the CAPA plan.

5.12.3 A complaint received by either party on a contract manufactured product is shared with the other party inside 24 hours. The complaint investigation is run per the normal complaint handling SOP.

5.12.4 A complaint that points to a product safety issue triggers the site recall procedure. The Contract Giver takes the lead on any market action since it holds the marketing authorization.

5.12.5 Each party reports back to the other on the outcome of every deviation and complaint. The report is filed in the Contract Quality File for each product.

5.13 Periodic Review and Audits:

5.13.1 The Contract Giver audits the Contract Acceptor site at least once every two years. A focused audit may be called at shorter notice after any major deviation or regulatory finding.

5.13.2 Audit findings are classified as critical, major, or minor. The Contract Acceptor responds with a CAPA plan within 30 days of the audit report.

5.13.3 A Product Quality Review is prepared for every contract product every 12 months. The review covers batch yields, deviations, complaints, stability data, and change history.

5.13.4 The Product Quality Review is shared between both parties and signed by the QP on each side. Any adverse trend is put on the agenda for the next joint quality meeting.

5.13.5 A joint quality meeting is held at least once per quarter between the two parties. The Contract Manufacturing Officer calls the meeting and keeps the minutes. The meeting walks through open deviations, open CAPAs, and any upcoming changes.

5.14 Termination of the Contract:

5.14.1 A contract manufacturing arrangement ends for one of several reasons. Normal expiry, mutual agreement, product discontinuation, loss of GMP status, or a serious breach of the Quality Agreement are the typical triggers.

5.14.2 A termination plan is drawn up at least 180 days before the actual end date where possible. The plan covers final batch runs, sample retention, document archiving, and material disposition.

5.14.3 Any material belonging to the Contract Giver is returned or destroyed as per the instructions in the termination plan. A Material Return Record is filed for every shipment back.

5.14.4 Retained samples and batch documents stay with the Contract Acceptor for the full retention period even after the contract ends. This is required by GMP regardless of the business relationship.

5.14.5 A final sign off is given by the QP on each side to confirm that all open items have been closed and the file is ready for long term archive. This sign off is filed in the Contract Quality File.

5.15 記録：

5.15.1 Quality Agreement.

5.15.2 Vendor Audit Report.

5.15.3 Technology Transfer Protocol.

5.15.4 Technology Transfer Report.

5.15.5 Release Decision Log.

5.15.6 Change Control Request.

5.15.7 Contract Quality File.

5.15.8 Product Quality Review.

5.15.9 Material Return Record.

6.0 略語:

6.1 標準操作手順: 標準操作手順。.

6.2 品質保証（QA）： 品質保証。.

6.3 QP: Qualified Person.

6.4 GMP： 適正製造規範。.

6.5 CAPA: 是正措置と予防措置。.

6.6 PIP: Person in Plant.