GMP Quality Management System Manuals

Management of Change in Computerised System with a view to GMP Expectations

Quality management systems are at the heart of pharmaceutical manufacturing operations. This page is dedicated to outlining all the manuals necessary to develop the best-performing processes and fundamentals of quality management

During system development, a forum (e.g., Change Control Panel’) should be established to oversee change requests for the project phase. This forum will report directly to the steering group for the project. Normally, it will require at least two people, including the System Owner/Project Manager and Infrastructure.

For the operational phase of a system, a different forum will be required (e.g. ‘Change Control Board’)replacing the function of both the steering group and the development change control forum, and this should be chaired by the System owner or delegate (e.g. Application Manager).

Usually, it will require at least two people, including the System Owner, Application Manager or their delegates, appropriate, with technical, infrastructure and Quality Assurance representation where necessary.

Both forums should be competent to:

– Assess all aspects of the proposed change

– Recommend acceptance/rejection/deferral of the proposed change

– Assess the impact of any proposed change in terms of cost/benefit

– Define the scope of the validation/testing work

– Ensure that all key documents, including manuals, training and SOPs affected by the

– Change are amended, and that the change is complete

– Agree the work plan for an approved change

Access by Regulatory Authorities and Auditors to Electronic Records

Requests for electronic records to be provided to an inspector from any regulatory authority or other external auditing group should be handled based on a single set of principles as set out below.(This should apply equally to internal requests for copies so that the integrity of any copy can be assured.) The legitimacy of the request can be judged from the same rationale that would be applied if the record was paper-based and called for under any of the

GxP regulations or guidelines or other regulators’ published requirements. In practical terms, the formats of electronic records are often restricted by the system’s capability, and where this is the case, it should be made clear in the system documentation.

In general, it is good practice before an inspection to seek advice regarding the formats of electronic records that might be required by or acceptable to an inspector so that this can be checked against capability and expectations can be managed.

Records provided as part of a formal submission to the FDA must be“identified in public docket 92S-0251 as being the type of submission the agency accepts in electronic form. This docket will identify specifically what types of documents or parts of documents are acceptable for submission in electronic form….”. “Persons are expected to consult with the intended agency receiving unit for details on how (e.g. method of transmission, media, file formats, and technical protocols) and whether to proceed with the electronic submission.”

Evaluation of Contaminant Options for Packing of Solid Dosage Forms

The company’s product portfolio may include a wide range of active materials. Effective use of those activities requires a clear recognition and understanding of the hazards, how to manage the associated risks, and adequately control employee and patient exposure

Experience has shown that:

Historically, significantly different approaches have been taken to manage containment and cross-contamination reduction.

Uncertainty and lack of clarity regarding requirements can result in inconsistent design and operation standards application.

Several common questions affecting accommodation/control decisions have arisen from different areas of the Company. This has resulted in duplication of effort and the potential for application of inconsistent solutions.

Decisions affecting packing operations have sometimes been based on hazard or perceived hazard rather than risk. A specific example is products in the class“cytotoxic”. Whilst all products in this class “kill cells”, the mechanism of action and specific properties of individual products in this class may be different and may require different solutions to accommodate them.

Decisions affecting packing operations have sometimes been taken based on an inconsistent interpretation of GMP guidelines.

Key factors affecting the design and operation of packing facilities and equipment(existing or new) should include:

– Operator protection

– Environmental protection

– Protection of patients in the community

– Product-associated hazard and risk

– Company standards

– Engineering standards

– Packing engineering technology options

A project team with representatives from Manufacturing Strategy Group, Safety Management, Engineering, and GMP Compliance should be set up to identify the key issues and how to address them.

The main issues affecting the company are:

– For a multi-product company, the aim should be to build flexible multi-product facilities.

– Need to provide and use Company assets in a cost-effective way whilst maintaining the license to operate.

– Different design solutions carry different costs.

– Design decisions do not always take a rational and consistent view of regulatory issues (health/hygiene/GMP).

– Lack of clarity around the relative importance of hygiene, GMP and engineering issues leading to inconsistent/inappropriate design and operational decisions.

– Decisions have sometimes been made on the basis of hazard, or perceived hazard,rather than risk.

240 SOPs, 197 GMP Manuals, 64 Templates, 30 Training modules, 167 Forms. Additional documents included each month. All written and updated by GMP experts. Checkout sample previews. Access to exclusive content for an affordable fee.

Retention and Disposal of GMP Documents and Retention Sample

The Reference / Reserve sample shall consist of at least twice the quantity necessary for all tests required to determine its compliance with specification, except for sterility and pyrogen testing, where the quantity required to repeat these tests shall be retained only once.

The Reference / Reserve sample shall be retained and stored under conditions consistent with the product labelling and/or specification requirements. If no conditions are given on the label and/or in the specification, the samples shall be stored at controlled room temperature.

The Reference/Reserve sample shall be stored in the same primary container enclosure system in which the product is marketed or shipped, or in one with essentially the same characteristics (i.e., mimics the container-closure system); it is acceptable to use more miniature packs.

Reference/reserve samples of APIs shall be retained as described in Appendix A3. Reference /reserve samples need not be taken for intermediates. However, intermediate samples are typically taken and retained until stock is consumed and API released. Reference/reserve samples of APIs shall be retained as described in Appendix A3. Reference/reserve samples need not be taken for intermediates. However, intermediate samples are typically taken and retained until stock is consumed and API released.

Reference/reserve samples need not be taken from Raw Materials. However, individual sites may make the decision to keep some materials for investigative purposes. Typically, this will be the case for New Product Introduction/Technology Transfer materials or supplier changes. Consideration should be given to the criticality of the material in the production process.

Reference/Reserve samples need not be taken from water, gases or starting materials that are highly corrosive or very inflammable unless explicitly stated.

Reference/Reserve samples should be kept in accordance with the retention stated in Appendix A2 if the product permits.

For products marketed in the USA or starting material used for USA-marketed products, as a minimum, representative sample lots or batches of Finished Products shall be selected by acceptable statistical procedures.

The samples for Finished Products should be examined visually at least once a year for evidence of deterioration unless visual examination could affect the integrity of the samples. The examination results should be documented and maintained with other stability data on the Finished Product.

Certificate of Materials Supplied to GMP Receiving Site

The general process for awarding a certified status to material from a specified supplier site is based on the following items.

Quality Assurance Agreement (or for vendors only, a Supply Agreement containing a section detailing quality-related requirements) Periodic Audit.

Quality Review/Risk Assessment by each Receiving Site considering the following items:

– A review of analytical methods, specifications, etc., used to determine any potential impact upon Regulatory registrations.

– Approved Technology Transfer to the supplier by the site.

– Identification of the supply chain for the material (i.e. how the material will be delivered to the Receiving Sites).

– A review of material quality and supply performance based upon data/information generated by the Supplier and the site. This can be from other materials received by the site from the supplying site.

To maintain a status of ‘certified’, materials should be subject to a documented periodic quality review.

The existence of an approved Quality Assurance Agreement (or for vendors only, a Supply Agreement containing a section detailing quality related requirements) with the Supplier Site and a recent audit of the Supplier Site are essential prerequisites for the award of a ‘certified status’ to a material supplied to a site.

Preparation and Management of Quality Agreements (GMP Agreement)

During the development of a new product, it is often necessary to use the manufacturing, testing, packaging or distribution facilities and capabilities of the Operations site or external contractors.

When it is proposed to use a contractor during development that may be used for future commercial activities, i.e. a Strategic Contracted Supplier, there should be close collaboration between R&D, the New Product Manager, the Project Team and for chemical intermediates and active pharmaceutical ingredients.

Outsourcing and Procurement Group to ensure that the contractor is acceptable for development and commercial supply.

The QA representatives should approve the Quality Agreement at the respective sites on behalf of the “GIVER” and “ACCEPTOR”. In addition, the site functional representatives should also approve the Agreement. Where the “ACCEPTOR” does not have a dedicated QA resource, then the functional signatory includes approval for all aspects.

Within the EU and where an Agreement is prepared to define the responsibilities of Qualified Persons for different manufacturing steps of an Investigational Medicinal Product as required by Annex 16 of the EU GMP, the Agreement should be signed by a Qualified Person at the respective sites.

Procedure for Quality Management at Contractors

For contractors not previously used to manufacture, supply, test and/or distribute sponsor’s materials/ products, the QA representative of the Lead Site shall:

– Could you agree on the QA contacts between the sponsor and the contractor?

– Share the principles included in this Procedure and the criteria for certification with the contractor.

– Could you audit the contractor with reference to the activities to be included in the Quality Assurance Agreement?

– Develop a Quality Assurance Agreement with the contractor and either approve the Agreement on behalf of the sponsor or identify the person who shall approve for the sponsor.

– If required, develop with the contractor a GMP improvement plan to address any deficiencies highlighted during the earlier assessment and agree on the process for monitoring progress and maintaining regular contact with the contractor for QA issues.

For contractors previously established to carry out similar activities for the sponsor’s products, the Lead Site will assist the Quality Assurance Agreement Co – ordination Site in updating the Quality Assurance Agreement and other information mentioned above to include the needs of the additional material/product to be manufactured by the contractor.

The Lead site, in consultation with the Quality Assurance Agreement Co – ordination Site, shall agree with the contractor on how links will be maintained between the contractor and sponsor’s QA processes, such as:

– Manufacturing Change Management Process (MCM)

– Dossier Management group will maintain the currency and accuracy of CMC Dossier for internationally sourced or internationally marketed products(s).

– Labeling changes

– The commercial stability program, including timely Out of Specification (OOS) reporting and periodic data reporting.

– Product Defect, Customer Complaints and Product Recall procedures.

– Annual Product Reviews.

– Sponsor’s Legal Affairs shall review any new Quality Assurance Agreement.

– Quality Assurance Agreements shall also be reviewed by the Toll Manufacturing Manager in Supply and Manufacturing to eliminate conflicts concerning tolling arrangements.

Guidelines for Regulatory Inspections at a GMP Site

It is essential that management develop, document and implement procedure(s) for managing inspections by Regulatory Authorities to protect the legal rights of the business (and the Regulatory Authorities to perform repeated inspections) and, at the same time, to maintain a professional relationship with the regulatory authority conducting the inspection.

Senior Management at a site or function must be present during key parts of an inspection. Inspection notification, ongoing highlights of the inspection, and the final results of an inspection must be communicated to relevant Senior Management in a timely manner.

A local SOP must describe the actions and responsibilities associated with an inspection. The SOP must address the local legal requirements for taking photographs, the use of tape recorders or other electronic equipment, the listening to, reading and signing of affidavits by company personnel, the review of internal audit reports and allowing access to computer databases.

Quality and Compliance Auditing at GMP Facility

QA/Compliance Groups should, in conjunction with management:

Establish a program of audit that satisfies the relevant standards / GXPs and covers all areas of their activities to a defined frequency. The audit program should ensure areas of highest risk are identified and covered.

Could you make sure that the program is undertaken to plan, with any changes to the plan being justified?

Please make sure any corrective/improvement actions identified during audits are implemented in a timely manner.

Please make sure any audit trends are identified, communicated and acted upon.

Ensure any Critical Observations or Trends are reported to Management

Management is to ensure that areas where systems/processes cross ‘functional boundaries’ are covered by audit when appropriate. Written ‘Quality Agreements’ should define auditing roles and responsibilities for audits jointly undertaken or performed on behalf of another group.

Management should establish an audit program that provides high-level audit coverage of the business.

In all cases, the QA/Compliance groups and relevant management have the responsibility to ensure adequate resources are available to ensure a comprehensive, effective program of auditing is set up, executed and followed up.

GMP Auditor Training Guideline

Auditors have a personal and professional duty to keep their knowledge and experience up to date with the current GMP and ongoing trends in pharmaceutical quality management, development, manufacturing and technology used within the industry.

The management must provide periodic in-house training events, presented using modern communication tools like audio – /video conferencing. A nominated sub-team should organise this and include topics from the internal and external environments that are relevant to auditors.

Joint audits can also be used as continuous training and harmonisation of audit performance when there is a clear justification and added value for the business.

The need for training must be regularly evaluated by local QA Management. During the annual performance and development planning sessions, any additional training courses in specific subjects/areas and/or refresher training should be discussed between the auditor and their line manager.

Compliance Improvements Plans Relevant to GMP Facility

Management review of compliance status and input to the CIP may include:

– Management review of compliance status and input to the CIP may include: Quality and Compliance Objectives

– Quality and Compliance Manual

– Standards, Procedures and Guidelines

– Applicable external regulations and guidelines

– Inspection and Audit observations and responses

– Compliance Management Group Information and Action Bulletins

– Quality and Compliance Key Performance Indicators (KPI)

– Adverse trends

– Corrective and Preventive Actions (CAPAs)

– Customer Complaints, Deviations or errors

Where areas for improvement are identified, Quality Risk Management should be used to prioritise items for inclusion in the CIP.

Archiving, Disposal and GMP Record Management

Retention Samples: Each function, department and/or manufacturing site (or designee) must manage its own records so that they are accurate, protected, useful, and readily accessible whenever they are needed.

Except for electronic records that are routinely backed – up, the company should, as a general rule, archive only one official record. Any duplicates (including copies distributed or held by other functions, departments and / or manufacturing sites) should be destroyed as soon as the immediate need for them has been expressed. Exceptions are official copies, which are archived instead of originals.

Wherever possible, records should be kept in their original form first defined in SOPs. For complete compliance, metadata associated with GXP electronic records, including audit trail information, must be archived with the records.

When electronic records are to be archived, all procedures must be thoroughly evaluated, tested and documented in collaboration with relevant Information Services organisations.

The microfilming, scanning, or otherwise copying of original records for security reasons does not automatically allow for the subsequent destruction of the original. The only exception to the above statement arises when there is a short-term life expectancy of the original record, e.g., the fading of heat or light-sensitive instrument output or the discontinuance of a computerised system holding the original records in electronic form. In such cases, producing an alternative form of the original record and declaring it an ‘official copy’ is acceptable.

The reasons detailing the business’s need for making the ‘official copy’ and then destroying the original record must be archived, together with a record of the date when the original was destroyed.

Where ‘archiving’ is not a mandatory requirement, it is recommended that any records that need to be retained for a specified period of time be kept in a secure storage location, which may, in fact, be the local archive.

GMP Audit of a Distribution Site

Once audit responses have been received, the Lead Auditor will:

– Review the responses for acceptability

– Incorporate responses into the report

When only minor observations have been reported, the audit will be considered closed, and the Final Audit Report will be issued.

When major or critical observations have been reported, the audit will be considered closed after the lead auditor confirms that follow-up commitments to major or critical observations(as specified in the action plan) have been completed. The Final Audit Report will be issued after you get the confirmation.

If longer-term corrective/preventative actions are transferred to a Compliance Improvement or Enhancement Plan for the distribution site, the Final Audit Report may be issued after receiving the Compliance Improvement or Enhancement Plan.

Obtain confirmation that follow – up commitments to major or critic observations have been completed (or obtain the Compliance and Enhancement Plan for longer term corrective /preventative actions).

Could you issue the Final Audit Report?

The Final Audit Report will be issued as an attachment to an e-mail. The recipients will be the same as for issuing the Draft Audit Report.

Supplier Auditing for GMP Facility

A questionnaire may be sent out to the supplier. Copies of the supplier’s laboratory test methods for each material supplied to the receiving site should be requested from the supplier if these have not been provided previously. If already provided, the supplier should be asked to let them know that these are still current.

The Lead audit Team (LAT) should identify that the site has received material/product from the supplier.

The LAT should distribute the latest information on laboratory test methods to the site for its review. The receiving site should let the auditor know of any issues/concerns about these methods or changes made to them by the supplier for discussion with the supplier.

The LAT should collate data on the supplier from other receiving sites (if applicable, supply history since the last audit, quality issues provided by other receiving Sites, etc.) and review the most recent questionnaires/audit actions.

The LAT/QA Site should request this information by sending the ‘Pre-Audit Information Request’ form to the other receiving sites. Any quality issue raised by RS should be indicated in the form. Input from other functions. i.e. Purchasing, Process Development, etc., should also be sought.

The LAT/QA Site should contact the supplier at least one month before any audit, arrange the audit date(s) and agree upon the supplier’s materials/services site(s) to be audited.

The LAT/QA Site should agree with the audit team (Note: 1). They may need technical assistance if the audit is on a specialised topic. Note: 2) Only appropriately trained staff should lead the audit), and define the scope of the audit. The receiving site may nominate a representative as a member of the audit team.

The plan (or agenda) for the audit should be proposed by the audit team, and details (e.g. travel, name of auditors, etc.) should be finalised with the supplier, who, in turn, may need to arrange for an expert to be present for the audit. The draft plan is only a guide, and subjects may change depending on findings(this should be stated in the plan to the supplier).

Management of Master GMP Document

Once approved, the master GMP document must be returned to and retained by authorised personnel. Access to the master must be restricted.

Where appropriate, the master GMP document must be retained in a secure archive.

A copy of the master GMP document may be taken and made available for use. For example, a master SOP and master batch manufacturing record may be copied and distributed for use.

In some cases, however, the master document may be the working copy for a given GMP activity, for example, protocols for validations and/or qualification. Procedures for controlling these documents, for example, documenting the location of and accountability for the document, may be required.

This is particularly important during the final review/approval of completed documents, as this may involve staff outside of the immediate location of the GMP activity.

Where the master document is used to generate the working copies, the reproduction process must not allow any errors to be introduced or any reduction in clarity or legibility from the original. The master and copies taken from it must be distinguishable.

Where work is undertaken by a third party on behalf of the GMP function, department or site, clear responsibilities for preparing, issuing, using and archiving the master must be defined in a Quality Agreement (contract).

Artwork Creation & Control of Printed Packaging Components

Packaging sites should have written procedures in place that describe the processes and responsibilities for:

– The receipt of approved artwork (from a Marketing Company or from the site’s own Graphics Unit)

– The supply of artwork to printers

– The receipt and quality assurance of printed components

– The release of printed components for packaging operations

– The correctness and quality of text and graphics that may be printed during packaging.

These should include change control procedures to manage securely the replacement of superseded versions of artworks, printed components and associated packed stock with new approved versions in a timely and regulatory compliant manner, together with the destruction of obsolete printing plates, stocks of printed components, etc.

The procedures should also address the processes and responsibilities for the printing, quarantining and supplying samples of new or revised printed components that may have to be produced to obtain approval from regulatory authorities/agencies before they can be used in finished products.

Release of API Bulk Formulated Products & Part Finished Packs

Any recorded abnormalities, observations, Out of Specification (OOS) results or deviation reports must also be reviewed before determining the batch’s disposition. Investigations will need to extend to other batches of the formulated or packed product and API as necessary to ensure that no other batches are implicated.

I would need to prepare a written record, including identification of the root cause, conclusions and follow-up, to confirm that the investigation has been undertaken.

Computerized Systems Risk Management

A risk-managed approach to the system life cycle is necessary for an efficient and effective way of working. Utilising risk management methodologies allows validation activities to be appropriately scaled to meet business and regulatory needs without creating unnecessary work. Documentation and testing are focused on appropriate areas to mitigate risk. In some cases, this may require additional testing in high-risk areas.

This approach also benefits the change control process because areas of regulatory impact and risk will have been identified prior to initiating the change. Thus, the impact of a change can be more easily identified and appropriately handled.

A number of assessments are carried out, and decisions are documented to support a risk-managed approach. It is essential to recognize that these assessments are tools to aid the team in the decision-making process. The output of an assessment should be carefully weighed against the team’s knowledge of the computerised system to make informed decisions. The team’s subjectivity will be instrumental in many cases throughout the process. Decisions should be appropriately documented to capture the rationale.

The scope and amount of validation or qualification is determined by assessing the business requirement, the associated activities and the level of risk this represents to the business. This is described in the following sections.

Batch Confirmation Certification & Release by a Qualified Person within the EU

A (Qualified Person) QP within the EC/EEA must certify each batch of finished product before being released for sale or supply in the EC/EEA or for export. This is to ensure that the marketing authorisation requirements for the manufacture of the finished product batch have been checked. The principles for Certification by a Qualified Person and Batch Release as outlined in Annex 16 to the EU Guide to Good Manufacturing Practice for Medicinal Products: “Certification by a Qualified Person and Batch Release” will apply.

When considering how to perform the duties required to certify a finished product batch, the QP will need to consider the type and number of operations being performed. On sites where the operations are many and complex and therefore, it is not possible for the QP to take direct responsibility for all or some of these routine duties, the QP will rely on the knowledge and expertise of nominated delegated QA professionals known to him or her to carry out these activities. The QP must ensure these tasks are performed satisfactorily.

Cross Contamination Risk Evaluation Process for Commercial Compounds

A company with a portfolio of products with a wide range of pharmacological potency, its manufacturing strategy usually involves the frequent use of multi-product facilities (both in-house and contractors). Therefore, in reviewing sitting and accommodation options for one product, the impact of that product’s pharmacological potency must be considered when evaluating the potential impact of carry-over of that product to other products manufactured in the same facility.

To assist Operations and R&D Functions with unusual or potent product accommodations (including accommodations at contractors) decisions, the Drug Safety Review Committee should exist to ensure that products (drug substance and drug product) are manufactured in a manner that minimises patient risk through cross-contamination from products manufactured in the same equipment, manufacturing plant or facility. The committee is, therefore, a support mechanism for sites/ functions to assist with difficult equipment cleaning and product accommodation issues.

The committee comprises representatives from Supply Chain, Drug Safety, Compliance Management and members from Operations, R&D as appropriate

Creation of Certificate of Analysis & Certificate of Manufacture

When materials are made at one manufacturing site and then shipped to another site for further processing, two critical pieces of information must be transferred between the QA units of the sites involved:

– The analytical results.

– The confirmation that the batch has been made in full compliance with GMP and Marketing Authorization/ NDA requirements

Analysis of the drug substance or finished product usually takes place at the manufacturing site and is not repeated at the subsequent processing site.

Analytical results are transferred to the next site in the processing chain either via a Raw Material CofA for transfers of drug substance or via an Internal CofA for transfer of finished product.

The Internal CofA must not contain acceptance criteria for more than one market. If, at the time of manufacture of the bulk finished product, the final destination market is unknown, the material should be supplied with an Internal CofA suitable for the country of the receiving packing site. Once the final destination is known and if the original Internal CofA is not suitable, then a market-specific Internal CofA should be requested.

The QA unit at the manufacturing site ensures manufacturing has occurred according to GMP and regulatory license requirements. Confirmation of batch compliance is then given on the Raw Material CofA or the Internal CofA.

The product is suitable for use in all markets unless a market restriction applies. Any such restriction must be given on the Raw Material CofA or Internal CofA using either:

– ‘Suitable for use in ……..’

– ‘Marketing Authorization excludes supply to market(s)……..’

Annual Product Quality Reviews (Periodic Product Review)

The scope and set-up of the Product Review report can differ depending on which product and market it covers. Below is a guide to this.

The Product Review report covering US products (Bulk bulk-formulated products, Drug Products and Finished Products) should be product or product family-specific.

The Product Review report covering EU products or products manufactured in the EU but intended for export only (Bulk Formulated Products and Drug Products) may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc.

The Product Review report covering API may be grouped similarly to the report covering EU products.

The Product Review report covering EU Finished Product packaging steps may be grouped by packaging line or packaging type.

If a site supplies both EU and US, a combined report should be considered f or products using the same process and master formula.

Warehousing and Distribution of Commercial Products

Written procedures should describe the different warehousing and distribution operations, including:

Cleaning and maintenance of the premises (including pest control)

Receipt and checking of the deliveries

Storage, including monitoring and, where necessary, control of the storage Conditions.

– Transportation conditions

– Stock security on site and in transit

– Withdrawal of stock from saleable distribution

– Records, including records of orders & distribution

– Handling of returned and recalled products.

– Management of personnel (including training)

– Management of product shipped ahead of clearance

These procedures should be approved, signed and dated by the person responsible for the quality system.

Utility Standards for GMP Manufacturing Site

General GMP Requirements:

The HVAC system must be designed appropriately to the products (APIs, intermediates, investigational products) handled and operations performed.

Manufacturing area HVAC systems must prevent the infiltration of contaminants from external sources including recycled exhaust air, and cross contamination between HVAC systems must be avoided. Additionally these systems require qualification/validation and change control procedures.

For warehousing and product storage areas, temperature monitoring and where appropriate temperature control is required. Building Management or Monitoring Systems used to control and monitor critical HVAC data in classified areas must be validated.

Air Quality:

The air quality needed in classified is based on the products handled and operations performed.

Air quality and air classifications for non-sterile operations must be designed to follow appropriate regulatory requirements and industry practices. For APIs the level of product exposure and the point in the manufacturing process should be considered when defining the air quality required.

Additional restrictions must be defined when handling, processing and storing highly potent materials such as antibiotics, hormones, radioactive materials or cytotoxic compounds. In addition, products that could cause potential allergic reactions, such as penicillin and cephalosporins, must be effectively controlled via the use of dedicated and separate facilities. HVAC systems serving microbiological lab oratories must be separate from HVAC systems serving production areas.

Conducting Investigations in GMP Environment

Investigation Approach:

Once the need for an investigation is identified, the investigation approach should be clearly defined and documented. Depending upon the extent of the investigation, this may be outlined in an investigation protocol to state the scope, timescales, and responsible individuals.

To execute the investigation, a team should be established to include experts from relevant local and remote functions as necessary. The investigation may be coordinated by centrally based organisations via Issue Management Teams.

Root/Assignable Cause Analysis:

Investigations must include steps to identify the root or assignable cause of the incident, problem or deviation. Where a root cause is not identified, the most probable cause(s) must be identified and corrective and preventive actions initiated on this basis.

Investigations should be detailed, focused and logical in pursuing the cause of an incident, problem or deviation. Investigation procedures should outline the general approach to be taken in conducting an investigation and require a review of relevant information, including records, data, past issues, and any events/circumstances leading to, surrounding and/or associated with the incident, problem or deviation. Where the initial investigation results do not lead to identification of a root cause, further investigation may be required.

Management and Documentation of GMP Training

All personnel must be aware of and be trained in the quality regulations, procedures, guidelines and company standards applicable to their area of responsibility. They must receive basic, job-specific, continuing and refresher training relevant to their needs and appropriate to their duties.

An employee’s formal education, previous training and experience should, together with the requirements defined in the job description/role descriptor, form the basis for defining the individual training program.

All trainees should be supervised until they are assessed as competent to do tasks independently. Records to demonstrate successful completion should be available before individuals independently doing critical tasks.

Definition and Documentation of Raw Data

Raw data are defined as any worksheets, records, memorandum, or notes that are the result of original observations, findings, measurements or activities. This Guideline deals with those raw data that are necessary for the reconstruction, evaluation, and/or assurance of the integrity of a process, work project or report.

Raw data may be in the form of paper, computer-readable media, magnetic media, photographs or film, microfilm or microfiche. Raw data may be created through handwritten notes, dictated observations, recorded data from instruments, data entered directly into a computer either manually or through an instrument interface or data printed automatically from devices.

Risk Management in the Quality and Compliance Area

Heads of Function, Process and System Owners and Project Leaders are responsible for ensuring that risks to quality and compliance are considered, understood and managed appropriately within their organisation, project or area. They must ensure that a suitable Quality Risk Management process is implemented and appropriate resources with the necessary competence are involved. They must also ensure the involvement of all stakeholders.

The approach to managing quality risks should be as simple as possible and commensurate with the level of risk.

Quality Risk Management activities may be undertaken by teams dedicated to the task. These teams will vary in size depending on the issue being addressed but should include experts from the appropriate areas involved and stakeholder representation. They should also include an individual knowledgeable of the quality risk management process and competent to apply any specific tools used.

Heads of Function, Process and System Owners and Project Leaders are responsible for ensuring that there is a process for reviewing and approving documented quality risk assessments and that appropriate records are retained.

Risk assessments relating to compliance issues will always require approval by Quality Assurance (QA). For development activities, QA may be involved in the approval process, and this will be assessed on a case-by-case basis.

Deviation Management for Pharmaceutical Manufacturing Site

There must be a local procedure to describe the steps to be followed to investigate and document deviations and to prevent premature batch release.

The local system must ensure that all deviations are adequately addressed according to the seriousness of the deviation and that the appropriate corrective and preventative actions are taken. The originating area and Quality Assurance must agree on the corrective and/or preventative actions. Deviations must be classified and investigated according to their seriousness as Level 1, 2 and 3. Appendices 1 and 2 identify the minimum reporting requirements and the critical steps in the life cycle of a deviation.

For Level 1 deviations, the root cause must be identified wherever possible, and a formal root cause analysis should be done if the root cause cannot be readily identified. If, following analysis, the root cause cannot be identified, the most probable root cause should be identified. The identified root cause, or the most probable root cause, should be used to define preventative actions to prevent recurrence.

For Level 1 and 2 deviations, a formal investigation should be performed, and the root cause identified. Level 3 deviations are, at a minimum, usually only documented in routine batch or test-related documentation and records.

The process and timing in which agreement and approval are achieved may vary depending on the level of the deviation. The exact approach should be described in local procedures. For example, for a Level 3 deviation, a retrospective review by QA in connection with batch release is acceptable. However, for a Level 1 deviation, corrective and preventative actions should be agreed upon with QA as soon as reasonably practicable after the incident.

Guideline for Development and Contents of Specifications

The author of the release specification is responsible:

For writing the specification document in a timely manner so that it is ready (and valid) before the release of material for clinical studies . Generic specifications following the requirements for phase 1 (outlined in Appendix 1) may be used at early stages of development. At early development stages, analysis may have been performed before the existence of a valid release specification, e.g. Campaign 2 drug substance.

For consulting with the relevant people within project teams or sub-teams as appropriate (e.g. ED, AD, PD, R&D, CMC Documentation, QA) and/or line functions according to local routines.

For the detailed contents of the specification. Standard requirements for an API/IMP or excipient are given in Appendices 1 and 2.

If the specification does not follow the standard requirements, e.g. those given in the Appendices, this should be justified/documented, e.g. in formally approved meeting minutes, a formal internal document “justification of specification,” or an appropriate history log.

A specific “function”/person (which could be the author) at the R&D site should be responsible for initiating, indexing and finalising the specification document and distributing it according to local procedures.

Manufacture Packing and Shipping of Materials Ahead of Full QA Clearance

When the material has been given a final full clearance at the supplying site, the QA Manager or deputy at the receiving site shall be informed immediately. This shall be done by a Certificate of Analysis, Analytical Report or an Electronic Clearance.

The material will be released when you get this clearance, providing all other routine controls are satisfactory. If the material is rejected, it is usually returned to the supplying site. If it has been agreed that the material remains at the receiving site, there must be:

– Appropriate controls in place for the rework or destruction at the receiving site.

– An agreement in place regarding allocating the rework or disposal cost.

– No contraventions of fiscal controls emanating from product ownership, e.g., under toll arrangements.

Determination of Storage Periods for API Excipients Intermediates and Raw Materials

Once an API has reached its retest date, it may be retested, and a new retest period may be assigned. Retesting is undertaken on a sample taken from the material stock. The new retest period shall be assigned based on:

– Available stability data

– Retest data meeting specification/results comparison with previous analysis

– Available retest data from previous batches

– Avoidance of ‘1 batch testing’.

– To assure continued suitability and not rely on 1 batch QC testing, build-up a stability profile for the API using extended stability studies. Where limited stability data is available, further supporting data can be obtained, such as :

> Analysis of samples from the stock of several batches of similar age

> An evaluation comparing impurity levels and profiles with original results

– Evaluation of the effect of ageing on the physical parameters of the material.

– Consider the final usage form of the product.

– Consideration of the conditions the API has been stored in Consideration of regulatory implications

– I would also like to give consideration to the use of stability-indicating methodology. The rationale used to determine the retest period shall be documented. The new retest date shall be calculated from the retest period added to the date of completion of the analysis.

– It is recommended that retesting shall be conducted by the same laboratory that conducted the initial release testing.

Management of Electronic Records and Electronic Signatures

Traditionally, records that are required for compliance with GLP, GCP and GMP or that will be submitted to regulatory authorities have been maintained on paper and, where required, authorised through the use of a hand-written signature on that paper. Modern automated systems allow us to perform record-keeping functions through the use of computerised systems, which may replace paper records entirely or in part.

In addition, it is possible to add an electronic signature to those records that serve the same purpose, have the same meaning and have the same legal significance as a handwritten signature.

Since these records and signatures are critical to both compliance and other business needs, it is important that processes and controls exist to ensure their integrity, security, and appropriate confidentiality. The use of electronic records and signatures is voluntary, and so it is still permissible to use manual record-keeping systems and sign records on paper using traditional controls, although this may, in many cases, be considered cumbersome and less cost-effective.

Wherever it is practicable, new systems that employ electronic records or signatures should not be implemented until full compliance is achieved. It is recognised that where commercial off-the-shelf software is purchased, even where it is best available for purpose, it may still be some time before a fully compliant version is available. In these situations, the gap between the system as it stands and a state of compliance must be analysed, and the associated risks assessed.

An action plan, approved by local management and reviewed or approved as appropriate by QA, should be developed to include any operating procedures or other stop-gap measures that can be employed to manage the risks from noncompliance and the proposed steps to achieve compliance ultimately.

I think this should include, where feasible, notifying the vendor of shortcomings. Just so you know, the vendor from the vendor regarding future upgrades should be kept.

The System Owner must be fully aware of the business and regulatory risks associated with implementing and using a not inherently compliant system and be prepared to own and justify those risks.

Any new system should include the relevant requirements defined by 21 CFR Part 11 in its User Requirements Specification. These should include requirements on the supplier’s development standards and practices and the product itself. Developer education, training and experience; control over systems documentation.

Product Quality Complaint Handling

All GMP manufacturing sites should establish a formalised program for handling customer complaints. A comprehensive complaint-handling program should include the following elements:

– A written Standard Operating Procedure (SOP) for processing complaints;

– Individually numbered complaint files for each incident report received;

– When complaints are received orally, a system for documenting the complaint form the information such that it is complete, factual and not editorial;

– Directions for handling the complaint samples in an appropriate and safe manner;

– Complete evaluation and documentation of results, including assessment of health risk, if any;

– Evaluation, documentation, and final disposition of the potential adverse event complaints.

– Review of relevant data and summary of findings to include a conclusion and/or corrective actions (with effective dates);

– Preparation of an appropriate response that includes results of the investigation;

– Review of the completed file, communication of the response to the complainant and maintaining a copy of the response in the file;

– Complaint files should be located in a designated area (accessible to the manufacturing area if kept offsite) and maintained according to the site’s record retention policy.

– Complaint review and analysis for trends should be conducted and reported to senior management and affected departments (Sales, Marketing, Production, Product Development, Legal, Packaging, etc.) periodically.

– Computer systems used for report management and/or trend analysis should be validated.

– In addition, when necessary, the appropriate regulatory agencies and/or competent authorities should be informed if the site is considering action following possible faulty manufacturing, product deterioration, detection of counterfeiting, or any other serious quality problems with a product.

Application of Quality Risk Management (QRM) to Periodic Review of SOPs

There is no regulation that requires specific periods for review of SOPs. However, the required status for any SOP is to be current. The goals of any site are to ensure it will continue to produce quality products and to meet the challenges of a regulatory inspection.

A periodic review of SOPs to ensure they are current is critical to meeting these goals. But this is a difficult task when SOPs may number in the hundreds or thousands at a given site.

A risk management approach to periodic review/revision of SOPs is recommended to ensure site resources are appropriately applied to meet this challenge.

The risk is the likelihood (PROBABILITY) of having non-compliant or deficient procedures that have the potential to impact product quality or regulatory compliance attributed to a lack of timely document review and that could remain unchecked or undetected. In addition, the greater potential of an SOP to impact product quality and regulatory compliance directly corresponds to a greater likelihood of that SOP being reviewed during an inspection.

The potential undesired consequence (OUTCOME) under such circumstances is a negative impact on product quality and a regulatory citation for having an SOP in a non-compliant status. Considering the number of SOPs that could be subject to periodic review at a site, a more practical approach is to categorise the SOPs based on potential impact on product quality and regulatory compliance.

Categorisation of SOPs Site-level SOPs may be grouped into:

– Quality

– Validation and Qualification

– Production

– Packaging and Labeling

– Materials

– Laboratory

– Facilities, Equipment, and Utilities

Quality Risk Management Application Critical Instrument Calibration

Human safety – Direct threat to human safety defines the most severe consequence of calibrations Out of Trend (OOT). If an instrument reading (or alarm) is the main protection against severe or potentially fatal injury, such as breathing air, oxygen level, or lethal compounds monitor, then severity is potentially high.

The severity of this risk will depend on whether an instrument is a primary component in a safety system or part of a redundant system.

Environmental safety – Instruments that prevent or alarm conditions of hazardous chemical release are examples of this risk. Whether these instruments are the sole indicator of environmental releases or an instrument has back-up or redundancy will determine the relative severity of risk due to environmental safety.

GMP (or GxP) compliance – Typically, evaluation is made during Commissioning & Qualification to determine the GMP impact of systems and components.

If an instrument’s performance is integral to demonstrating compliance with product specifications, then the risk severity is based on whether the data derived represents the sole measure of an attribute or whether the attribute is further assessed through another measure or test later in the process.

Instances, wherein an attribute is further characterized by testing performed further down in the process, may determine a lower severity ranking than instruments that determine compliance to specs without further verification.

Structured On - the -Job Training System

On the Job, training can be defined as the one-to-one process of providing and mastering knowledge and skills to perform a specific task within a job, with the following characteristics:

– Occurs in the actual or simulated workplace;

– Uses a predetermined training sequence (structure for the training should be documented and approved prior to execution);

– Requires the active presence of a trainer and trainee;

– Uses materials and guides; and

Employs a systems approach, with practice opportunity and demonstration of competence. Structured Job training provides employees with the knowledge and skills required to perform job functions in accordance with approved SOPs and other instructional materials. The Job training includes but is not limited to, technical skills training and sequential steps to perform tasks within predetermined criteria. For example, On the Job training practices can be applied to tasks such as batch record review, environmental monitoring techniques, internal audits and other job functions that require acquiring a new skill

Typically, there are five phases to a Structured On the Job Training System:

– Preparation of the Structured On the Job Training Process

– Introduction

– Knowledge & Skills Training

– Practice Sessions

– Training Assessment

Training System for Aseptic and Preparation for Aseptic Operators and Support Staff Highly trained and skilled operators are critical to the quality of the aseptically produced product. Their training and understanding of their role will lead to successful or detrimental effects on final product quality. EU Annex 1 states, “Much depends on the skill, training, and attitudes of the personnel involved.” The Aseptic Processing Guideline recognises that poor personnel practices can compromise even the best-designed facilities.

Those working in and preparing equipment and components for aseptic processing must understand basic microbiology and APA grades, the potential impact of non-sterile products on patients, and their role in ensuring that the production environment and product are maintained with the necessary integrity and quality.

FDA’s Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing, calls for knowledge and/or skill-based training on aseptic technique and clean-room behaviour, basic microbiology, gowning techniques, personal hygiene, and job-specific training.

A critical aspect of training not specified by either of these documents is education on the overall process for producing aseptic products.

Knowledge-based training is critical so that operators understand the overall production process, their critical role, and the special considerations that need to be given to any sterile drug administered through injection or IV.

Skill-based training develops specific job skills so operators can carry out tasks to the required specifications every time.

Disposal of Rejected and Waste Materials

Rejected and Waste Materials, Prior to Destruction or Shipping for Destruction, should be rendered unusable following applicable local regulations to prevent misuse of such materials.

Examples of these rendering practices are as follows:

– Printed materials are defaced or shredded to a size small enough to be obvious to the casual observer that the material is not intended for use and cannot be easily diverted for use;

– Packaged products or bulk products (i.e., drums or boxes of bulk tablets) are shredded or ground to a size small enough to be evident to the casual observer that the material is not intended for use and is in a condition where diversion and use would be a difficult and unappealing prospect;

– Bulk products (i.e., drums or boxes of bulk tablets, APIs) are wetted to achieve partial dissolution or mixture with quantities of other wastes to make the entire mass impractical and unappealing for diversion;

– Medical devices are ground or crushed to render them unusable;

– Drinkable alcohol is rendered unusable by adding denaturants, extensive dilution, or mixing with other waste solvent;

– Labeling, including labelled, empty product containers and similar items, and labelled product waste is destroyed or defaced with permanent ink crosses to prevent unauthorised off – Site salvaging or use or

– On-site incineration.

Material Status Indication

All Status Label Sizes and Shapes should be square or rectangular and the same size except for sampled status labels, which may be smaller. Alternative measures for the use of status labels, except for Rejected and Sample status labels, may be used. Additional points regarding the use of status labels include:

– Standard size may vary from Site – to – Site;

– Print size may vary, but must clearly display status;

– Validated bar-coding systems can be used to augment status labeling as long as the status is clear and visible;

– Approved status labels are not recommended for finished API packaging or drug product or medical device shippers; the action would require peelable labels, which tend to fall off containers. In addition, when materials are transferred to another Site, such status becomes misleading, and Label entries are made before application unless otherwise authorised by the responsible Quality Team.

Receipt, Approval and Use of Labels and Labeling

If Labels and Labeling are needed for Packaging Equipment Set Up, then the labels and labelling materials that are specified on the Packaging Batch Order for the current lot or batch to be packaged in the packaging area should be used.

The same issuance and verification and receipt and verification controls should be applied to all labels and labelling materials used for packaging equipment set up as used for the remainder of the lot or batch.

Labelled Products Removed from the Line or Conveyor but not from the Production Module (e.g., for equipment disruption) should be temporarily stored to preserve container/closure integrity and product cleanliness.

Control of the products removed from the line should be defined in a Site SOP. When Complete Labels or Labeling are Printed Online, the first and last units completing the packaging/labelling operation should be proofread by a qualified person against the approved copy of the master label or labelling and approved by the Site Quality Team.

Material Supplier Approval

The Supplier Audit Report should include, but not be limited to, the following information:

– Supplier name, address, type of operation, name of product or services supplied, and principal contact;

– Date of audit and date of last audit, if applicable;

– Purpose of audit;

– Site auditor and audit participants;

– Audit findings;

– Supplier Audit Rating; and

– Executive Summary (for the site use only).

Pest Control Programs

All Pest Control Treatments and Inspections should be recorded, and the records maintained in a manner approved by the Site Pest Control Coordinator.

Records should display the location, date, and time of treatment or inspection; the chemicals applied, traps and equipment inspected, the name of the individual making the application or inspection, and, when an escort is required, the name of the Site employee who served as an escort.

Raw Materials and Packaging Materials Receipt

Supplier Labels on each container or group of containers should describe the exact material ordered (including grade, if applicable) and the supplier lot number, if available.

The supplier labels should be verified during or immediately after unloading. If the supplier applies a label containing the site’s in-house material code, the label should also be verified during or immediately after unloading.

Water Purification, Storage and Distribution For Pharmaceutical Production

For Highly Purified Water (HPW) and Water for Injection (WFI) Systems, recirculating distribution loops should be maintained at >70 degrees C. Such heated distribution loops are considered self-sanitizing.

For HPW and WFI systems with distribution loops and/or storage tanks that are maintained at <70 degrees C, written system sanitization procedures should be followed that are based upon accepted sanitisation methods (e.g., thermal treatment) and should be validated.

Reduced Testing Program

For those risks that are deemed to exceed the site’s risk acceptance threshold, mitigation steps must be taken before proceeding forward with a change in the release testing process.

For this example, most mitigating actions will target the risk’s probability and detection components. A site may choose to work with a vendor to improve the compliance status of the facility supplying the material or aid in improving their process to improve the quality of the material received; both actions target the probability associated with a material.

To mitigate a high detection score, a site may implement in-process checks or tests to monitor the performance of the material. The process should proceed only when all risks are reduced to meet the site’s pre-defined acceptance threshold. This should be confirmed via re-application of the tool for risks that were the subject of mitigation efforts.

When all risks are judged to comply with the pre-established risk acceptance level, the document will be sent to the Quality Team for review and approval.

The documentation package should contain all documented aspects of the Quality Risk Management process. Implementing the proposed change in frequency cannot proceed until all approvals are obtained.

The risk assessment process should be repeated any time a change is introduced that impacts the practice, e.g., a change in the vendor’s audit status or a change in the vendor’s manufacturing site, process, grade of material sourced, etc.

GMP Training System

The overall role and responsibility of the trainer will depend upon their job function and the personnel structure at the facility. Colleagues may be full-time or part-time trainers.

Therefore, their responsibilities for training may be shared among others in their department or assisting departments. Generally, a site can define a Training System Owner, a full-time trainer, and/or a part-time trainer/department trainer/Subject Matter Expert (SME) separately.

GMP Training System Owner – the designated individual responsible for overseeing the effective, efficient and compliant implementation of the site GMP Training System.

A full-time trainer is someone with the education, training, and experience relative to the training topic and demonstrated competence.

These trainers may perform communication, knowledge and/or skills-based training. Typically, these individuals will be responsible for developing training materials, including presentation materials and training effectiveness assessments. These individuals may also be responsible for the Training Records System.

Implementation of Real Time Release

The Real-Time Release approach should be designed to ensure that the required critical quality attributes are achieved. Product release specifications include a test list, analytical procedure references, and appropriate acceptance criteria to ensure acceptable quality.

Real-time release testing may require moving to alternative analytical procedures and/or modifications to the acceptance criteria, where pharmacopoeia allows. However, the quality expectations for the product remain the same.

The regulatory submission will need to detail how the manufacturer justifies and complies with the release specification. The submission will need to describe how the data to confirm that the product meets specifications will be generated to take into account revised sampling and testing strategies.

It should be noted that eliminating the need to perform a specific test (based on scientific justification) does not necessarily justify the removal of the test listing from the product specification (e.g. if a compendial requirement exists). In this case, the submission should explain why the testing is not performed and sufficiently justify how real-time release testing and the control strategy will provide acceptable quality assurance and support the statement “will meet if tested”.

Offline testing with conventional methods is still required for end stability testing (i.e. shelf life testing/stability testing) as well as post-market surveillance ((e.g. complaints), where appropriate.

Therefore, a second specification outlining Shelf Life / Stability requirements may be required. Offline release testing may still be required routinely for attributes not covered by the Real Time Release strategy.

Preventive Maintenance Standards and Techniques in Pharmaceuticals

Like – for – Like Changes – replacement of a part with a part that meets the original specification in terms of:

– Functionality,

– Input Range,

– Output Range,

– Accuracy Specifications,

– Operational Specifications and

– Material of Construction.

– Non – Intrusive Condition Monitoring – inspection which does not require the equipment to be taken out of service, physically removed from the system or taken apart to access the condition (e.g. visual or audible).

– Predictive Maintenance Activity – an activity in which equipment inspections or monitoring is conducted using devices that access equipment conditions during normal operation (e.g., vibration analysis, oil analysis, thermography).

Assessment In Support of Eliminating Defined Shipping Temperature Range

During summer and in tropical climates, pharmaceutical products shipped under ambient conditions can potentially be exposed to elevated temperatures, reaching an approximate maximum temperature of 50ºC (122ºF).

A review of Central America to United States Distribution Centers shipment time indicates that the typical shipment time for these pharmaceutical products from manufacturing facilities to distribution centres is less than two weeks.

The presented reason may be applied to discontinue defined temperature range shipments for other shipping routes if the shipment time is known and falls within the assumptions of this model.

Identifying Testing Requirements, Patterns and Acceptance Criteria for Analytical Method Transfer

Where lots are not available with impurities at a level suitable for meaningful inter-laboratory comparison, strategies will be considered to adequately assess the ability of the recovery limit to detect and quantify impurities.

This may include spiking/recovery experiments, where appropriate. If a spiking experiment is conducted, and at least one specified impurity is available, recovery should be assessed at or between the Quantification Limit and Specification Limit.

For multiple-strength drug products made from a common or similar blend, only one dosage strength needs to be spiked.

If the historical data shows levels of an impurity in the lot identified for the transfer below the Quantification Limit but above the Limit of Detection (LOD), then it is recommended that the experimental plan include a requirement to perform multiple analyses (e.g. 3) of an un-spiked sample from the same lot and then use the average results from the un-spiked sample in the recovery calculations to correct for the presence of the impurity in the sample.

When impurities are unavailable, it may be acceptable to dilute a standard of the main component down to the Quantification Limit and perform a study to ensure that the recovery limit can achieve the appropriate levels of precision and sensitivity. Other strategies may be used as long as they are in the Transfer Plan.

Weighing Device Performance Testing Frequency Determination, Risk Management Approach

The quality risk management approach as applied to the evaluation of reduction of performance verification frequency illustrated in this guidance not only identifies the different risk factors to consider when performing the evaluation but also demonstrates a simple tool (depicted in tabular format) for determining how to group potential risks into low, medium, and high categories.

For the purpose of this evaluation, two risk factors, probability and severity, will be examined for each perceived risk associated with the defined risk scenario. From this evaluation of individual perceived risks, the cumulative risk profile associated with a potential change in frequency will be devised.

Through the application of a simple tool coupled with requisite background knowledge, it is expected that this assessment will serve as a model for GMP sites to standardise the evaluation of changes to the frequency of weighing device performance verification testing.