GMP Standard Operating Procedures (SOP)

Quality Assurance (QA) Management Procedures

Writing Standard Operating Procedure

Standard Operating Procedures (SOPs) are issued to specifically instruct employees in areas of responsibility, Work Instructions, appropriate specifications, and required records. SOPs outline procedures that must be followed to claim compliance with GMP principles or other Statutory rules and regulations.

Procedures can take the form of a narrative, a flow chart, a process map, computer screen printouts, or a combination of all or any other suitable form; however, they must be written in an appropriate, effective grammatical style. (e.g., plain English).

Classification of GMP Documents

In this SOP, you will find commonly used GMP documents such as quality and Technical/Master file records to build up a top-quality management system for your production sites, a description of documents & records, their distinction, acceptance requirements, and storage specifications. This process has schematic blueprints for your knowledge of how different records are prepared and saved in a common data source.

Quality Documentation Change Control

This procedure describes the role of manufacturing personnel, document control officers, and file administrators in creating and reviewing/updating quality documentation. All personnel involved in the manufacturing activities must read quality documentation and are responsible for creating and updating procedures when required.

Documentation Rule

There are many different reasons for the creation and maintenance of GMP documentation. Good Documentation Practice is required for one or more of the following reasons:

– Keep track of activities

– Create legal documents

– Provide a historical record

– Provide information

– Comply with regulations.

Document Control

A request to initiate the new document is received via a completed, signed Form 505 – document change request. See QMS 010- Classification, Definition, and Approval Matrix of GMP Documents to define document types and data required for each type. The Document Administrator is to:

Issue a document number from the Documentation Database. See SOP QMS 015 – Quality Documentation Management and Change Control for the SOP numbering system.

Raise a new record in the “Quality Documents” area of the Database. See Appendix 1 for a flowchart describing the process for raising a new record.

Complete file properties for the document to be created in the database. Type “To be Written” in the Status box with the author’s name and the date the record was added.

Master GMP Documents

Encompasses all documentation required for the manufacture and release of a product. The Master File encompasses both in-house and regulatory documentation, a description of which is detailed in this SOP.

Deviation Reporting

A deviation is a departure from standard procedures or specifications resulting in non-conforming material &/or processes or where there have been unusual or unexplained events that have the potential to impact product quality, system integrity, or personal safety. These deviations are investigated and recorded as a deviation report (DR) for compliance with GMP and continuous improvement.

Product Shelf Life

The shelf-life calculates the expiration date for products manufactured/packed at a GMP site. Shelf Life means the number of months or years the product will meet the label claim, plus a safety margin when packed and stored as specified.

Supplier Selection and Evaluation

The process of supplier selection and evaluation is divided into four phases.

Vendor Assessment

Phase 1. Technical discussions
Phase 2. General Vendor Audit
Phase 3. Item specific evaluation

Vendor Evaluation

Phase 4. Ongoing vendor evaluation

Vendor Certification

Certification – “Is the act of approving quality control testing results provided by the supplier about a specific material, thus eliminating the need to undertake some or all laboratory tests on receipt of that material unless specifically required to meet regional/local GMP and regulations.”

Product Complaint

Critical Complaint: A complaint that strongly indicates the purity, identity, safety, or efficacy of a product may have been compromised and has the potential to cause a severe or life-threatening health situation.

Serious Complaint: A complaint that indicates the purity, identity, safety, or efficacy of a product may have been compromised but does not present as a severe or life-threatening health risk.

Standard Complaint: A complaint that is neither critical nor serious.

Periodic Product Quality Review

The annual product quality review will determine the need for re-validation of processes or methods, changes in product specifications, manufacturing, and control procedures, and evaluation of the need for regulatory notification supplements to regulatory submissions.

Rework

In-Process Manufactured Goods: Re-inspection / Rework of In-Process Manufactured Goods due to a possible defect in all or part of the BPN (Batch Production Number). The batch number will remain the same.

Manufactured Finished Goods (MFG) Rework: Conversion of a product from one Batch Number to another. Re-inspection / Rework of Manufactured Finished Goods due to a possible defect in all or part of the BPN.

Rework of Product at Contract Manufacturer: Reinspection / Rework of Manufactured Finished Goods due to a possible defect in all or part of the BPN at an External Contract Manufacture site.

Product Identification and Traceability

A product traceability system allows for complete and up-to-date histories of all batches of products, from the starting materials to the complete final product. A unique and controlled numbering system provides identification and status of materials. The system can be interrogated to provide reports, allowing for full traceability.

GMP Audits

GMP audit is a systematic and independent review to verify compliance, suitability, and data integrity. Audits may assess systems, processes, procedures, facilities, products, records, and data for compliance with policies, standards, procedures, guidelines, regulations, or regulatory submissions.

Batch Documentation

An authorized production operator must ensure that all appropriate Batch (BPN) relevant records have been reviewed for completeness and included in the Batch Documentation.

Production operators have to print out the appropriate “Batch Documentation Checklist” Form for the Process being manufactured, complete the Production section of the Checklist, and include it at the top of the Batch Documentation.

Process managers have to ensure an effective process of Batch Documentation collection. QA staff must collect the batch documents and retention samples for QA Evaluation. Laboratory staff have to collect the test samples for laboratory analysis.

Batch Document Evaluation for Release

Batch documents: A collection of all relevant documents, including MI sheets, generated throughout the manufacturing process of a particular batch. It also includes samples of printed cartons, leaflets, shipper labels, and Line clearance/Opening forms collected altogether.

GMP Training

All manufacturing employees must attend a formal GMP induction training program at the commencement of employment to learn the principles of Good Manufacturing Practices.

Manufacturing staff is required to undertake ongoing GMP education to ensure continued knowledge of current GMP requirements. The GMP maintenance education points system is a means of ensuring this.

GMP Training Materials

Training materials play a vital role in ensuring that staff is fully competent to perform tasks that minimize risk to themselves, others, products, or company equipment.

House Keeping Audit

The level of housekeeping practice indicates someone’s attitude towards GMP and quality. This means:

– Thinking of SAFETY FIRST.

– Thinking GMP COMPLIANCE

– Wearing uniform and hairnet correctly.

– Minimizing the amount of equipment kept in areas.

– Do not clutter areas with unnecessary items or personal belongings.

– Emptying bins and removing waste.

Contract Work

cGMP and all aspects of this procedure must be adhered to to ensure the production of a quality product. Separate documentation is to be prepared for each presentation of each type of product. Still, repeat operations are referenced to the original documentation as long as there has been no change in the items listed. However, any changes to established contract work will be handled similarly to new contract work.

Raw Material and Packaging Components Sourcing

This SOP aims to define a manufacturer and vendor, detail selection criteria and procedures, and provide details for assessing manufacturers and processes for their approval.

Quality Investigation Process

The quality investigation process is mainly built upon root cause investigation.

A batch record comment is a minor event, which is something that is expected to occur, is usually isolated to a single batch, the cause is known with certainty, no follow-up action is required, and is non-recurring within a short period. For example, line stoppages at certain times, etc

Change Management System

All departments requiring a change control management to a GMP system are bound by the rules set out in this procedure. This SOP applies to any change affecting product quality, regulatory filings, data integrity, or environmental health and safety.

Cross-functional investigation

The Scope of this SOP covers Cross-Functional Investigations (CFI), also known as extended investigations. CFIs are raised when a deviation occurs, or there is a complaint trend, annual product review trend, or trend in any other quality aspect identified by a quality system.

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Quality Control Laboratory Procedures

Retest Dating

The period of time following analysis that a material can be used prior to retesting and setting a new retest date, provided the material has been stored under appropriate conditions.

Calibration of Laboratory Instruments

The control of calibration for measuring and testing equipment ensures that the measurement uncertainty is known and is consistent with the required measurement capability.

Laboratory equipment and instrumentation are handled and stored to maintain their accuracy and fitness for use. The SOP or Equipment Log defines any special handling or storage requirements applicable to each piece of equipment or instrument.

Archiving of Laboratory Documentation

A Certificate of Analysis refers to the results sheet accompanying any batch imported (external C/A) or locally manufactured product going out to Export countries. GMP documentation is any procedure, control, record, distribution, related record, or electronic file that must be retained as evidence of compliance with GMP.

Reference Standards

It is the responsibility of the Laboratory staff to use the Reference Standard to:

– Ensure its availability and use within expiry.

– Follow the relevant procedures in this SOP.

It is the responsibility of the Laboratory staff assigned to “Reference Standard Maintenance” to:

– Order primary reference standard.

– Order breakdown of product/impurity reference standards.

– Order any secondary raw material reference standard type 2 attained from within the internal and external sites.

– Order primary reagent reference solutions.

– Log and reference all reference standards received.

– Follow the procedures in this sop.

Laboratory Workbook

The principles of GLP are applied to the testing of chemicals to obtain data on their properties and safety regarding human health and the environment. The data is used to meet regulatory requirements.

Certificate of Analysis

The scope of this procedure is issuing a Certificate of Analysis or Certificate of Manufacture for products or materials distributed to customers.

A Laboratory staff is responsible for creating Certificates of Analysis and Certificates of Manufacture upon request, notifying the Technical department of any changes to Certificate Profiles, updating templates and locating archived data, and faxing, emailing, or mailing requested certificates of Analysis to the appropriate person. An Authorized Person is responsible for signing all Certificates of Analysis and Certificates of Manufacture.

Analytical Reagents

On receipt of purchased reagents, the date should be recorded on each container so that its approximate age is subsequently known. If multiple containers of one reagent have been received, they should be labeled ‘X of Y’ (e.g., 1 of 4, 2 of 4, 3 of 4, 4 of 4). The order book should also be signed off at this time, and the person who ordered the reagent is informed of its arrival.

An expiry date, as well as the opening date, should be added when the reagent is taken into use in the laboratory.

Laboratory Waste Management

To describe the disposal methods used for hazardous waste from the Laboratories. It is the responsibility of the Laboratory manager and Laboratory staff to dispose of hazardous waste properly according to the SOP.

Laboratory Retention Samples

This SOP will be followed by the Laboratory staff assigned to retention Samples in executing the collection, storage preparation, transportation, storage, and disposal of retention Samples. Quality Assurance staff responsible for checking and storing retention samples in the retention sample room will also follow this SOP.

Laboratory Supplier Approval

Where appropriate, the laboratory manager evaluates the purchase of equipment or instrumentation in consultation with the Laboratory staff, considering the requirements of the Test Method and safety legislation.

Laboratory Results Out of Specification Investigation

The Out-of-Specification test result lies outside the specifications to which it must conform.

Laboratory Testing for Raw Materials

– The testing of raw materials assures that quality materials are used in production.

– It is the responsibility of all laboratory staff to test raw materials according to this SOP.

– Proper documentation of all testing and testing procedures allows traceability and regulatory requirements to be met.

– In this SOP, raw materials include actives, excipients, and printed packaging components pending laboratory tests.

Laboratory Testing For Finished Products

Finished Goods test samples are collected by authorized laboratory staff from the retention sample room after signing the Test and Retention Sample log book, which is distributed to the appropriate teams and placed in the designated team sample drawers.

Stability Protocols

A stability Master plan is issued by the management team that details the stability studies required to maintain compliance with regulatory and GMP obligations and commitment, assigns each study to a specific Commercial Stability Site, and monitors the progress of the studies to completion.

Stability Trial Testing

The stability trial program is grouped into three (3) types:

– Annual maintenance stability

– New product stability

– Special studies (Trials)

Preparation of Disinfectant Solution in the Lab

The following safe working procedures should be observed:

– IPA is a FLAMMABLE liquid.

– Personnel using IPA for cleaning must wear Safety glasses and Sterile Gloves.

– Personnel preparing IPA must wear a full face mask.

– Special care is to be taken when handling the new 20L drum of IPA.

– Use the lifter provided to lift and move the heavy drums.

– Do NOT open IPA near electric devices/motors or other ignition sources.

– Do NOT rinse the inside of any vessels to be used for 70% IPA with HOT water. Only use 70% IPA or WFI.

Laboratory Analytical Determinations

This document is to be used in conjunction with the relevant test method. The criteria outlined in this document are minimal and must be used if the test method does not give the necessary information.

HPLC Reproducibility, Column Performance, and Testing Guidelines

Reproducibility or calibration tests are carried out on each HPLC system to measure system conformance before running assay tests. Column performance tests are carried out on each column to be used in an HPLC method to measure Column conformance before assay determinations. General HPLC testing guidelines have been included in this SOP.

HPLC Method Development & Validation Procedure

The validation of an analytical method is the process by which it is established that the method’s performance characteristics, such as Precision, Accuracy, Specificity, Linearity, Limit of Detection (LOD), Limit of Quantitation (LOQ), and Robustness, meet the requirements for the intended applications.

Laboratory In Process and Finished Product Quality Control

This procedure applies to receiving samples, scheduling tests, testing, reporting, reviewing, approving, releasing, and re-assaying the in-process and finished products in the QC Laboratory at a GMP site.

Laboratory Housekeeping and Glassware Cleaning

All Laboratory personnel involved with glassware cleaning, laboratory housekeeping, and housekeeping inspections must follow this procedure. The Laboratory Manager, Team Leaders, and all laboratory staff are responsible for ensuring that the laboratory housekeeping is maintained to an acceptable level of GMP/GLP.

Safety Procedure in Laboratory

All laboratory personnel should ensure that the work area is decontaminated before and after work commences and that it is free from objects not relevant to the work being undertaken.

Use and Control of Laboratory Chemical Materials

This procedure applies to laboratory chemical materials, including, but not limited to, chemical substances, solutions, reagents, cleaning solutions, and waste, both prepared within the QC Laboratory and obtained commercially.

Qualification of Laboratory Instruments

This procedure applies to all laboratory instrumentation used by the Quality Control Laboratory, all analytical instruments including all its modular components, or a single device with no modular components.

Sampling of Raw Materials, In-process, and Bulk Finished Products

This procedure applies to all sampling of Raw Materials, In-process, and Bulk Finished Products in the Warehouse during manufacturing and packaging operations.

Stability Management Procedure This procedure

applies to the initiation of stability studies (including stability protocols), obtaining stability samples, storage of stability samples, stability testing, results reporting, and result evaluation for the stability program.

Validation of Analytical Test Procedure

This SOP covers all analytical and biological quality control methods, non-compendial or compendial, that the Quality Control (QC) Laboratory uses to test pharmaceutical products in or intended for the marketplace.

This includes testing performed for the release or stability evaluation of Regulatory Starting Materials, Active Pharmaceutical Ingredients (API), Raw Materials (RM), In-process Materials, Medical Devices, and Finished Drug Products.

Microbiology (Sterility) Laboratory Procedures

Sterile Entry

Carefully roll down the leg part of the overshoe, exposing the inside while you are still wearing gloves. Slip out the foot and shoe and place the overshoes on the shelf or bench provided.

If preferred, the overshoes and safety shoes may be removed together, provided the foot can be slipped into both after the next gowning. This procedure cannot be carried out in Glass Sterile because glass fragments are carried into the change room on the soles of overshoes.

Aseptic Gowning Validation

After the sterile training session, the candidate will complete a full gowning session in the sterile scrub preparation room. He/she will be observed by a fully trained and validated Microbiologist and assessed according to the Checklist for Procedure for Entry into Sterile (Form 655 – Validation record for sterile gowning procedure).

This should occur within one month of training. It is the individual’s responsibility to book their own sterile gowning validation session with the Microbiology Department.

Microbiological Data Recording

The person conducting the test is responsible for recording all the information into a computer system, electronic record-keeping system, or the relevant books.

The type of information that should be recorded may include raw material tests, sterility tests, parametric release products, non-sterile tests, bioburden tests, water testing, preparation of media, autoclave charts, machine and line steaming charts, fallout plate results, bacterial endotoxin tests, and biological assay tests.

Biological Waste Destruction

Biological Materials: This includes media (both dehydrated and commercially prepared), diagnostic kits, such as a staphylase kit, LAL reagents, and live microorganisms. It also consists of all tested products and their containers and sterility room waste (Rubbish).

Depyrogenation of Glassware

To outline the procedure for the dehydrogenation of glassware using the microbiology laboratory qualtex oven.

Media Preparation

When dehydrated media is received in the Microbiology Laboratory, please record the date received clearly on the outside of the container. Distilled water must be used to prepare all media and collected on the day of use. Upon initially opening a media container, the date must be written clearly on the container. Preparation details are to be recorded in the logbook.

Micro. Integrity Leak (Soup) Testing

Media Fill Schedule: Media runs will be performed on all manufacturing shifts for each aseptically filling machine process at least twice yearly (every six months). This is to be conducted after significant modifications or maintenance. Terminally sterilized lines and non-sterile processes are done once per year/shift.

Aseptic Media Filling and Soup Test

It is the Microbiology Manager’s responsibility to set up a yearly schedule of routine Media runs. This schedule is a guide only and can be altered within reason to fit in with production requirements. To ensure compliance with the GMP, Routine media runs for aseptically filled processes (process simulations) are to be conducted at least twice per year per shift and process. It is once per year per shift for terminally sterilized lines and non-sterile processes.

Environmental and Plant Hygiene Monitoring

Daily monitoring of sterile grade areas during production is to be conducted by trained production staff. The Microlab is to ensure that the necessary plates are delivered daily so monitoring can take place.

Once a test has been completed, the responsible operator is to initial the plate and ensure that the batch’s Batch Production Number (BPN) running at the time of the test is written on the plate. Plates will be labeled with prompts to ensure this isn’t forgotten. If no batch is running at the time of the test, N/A should be put on the plate instead of a BPN.

Microbial Limit Testing Using Laminar Flow Cabinets.

This SOP describes the procedures for conducting microbial limit tests in the microbiology lab’s laminated flow cabinets.

Microbiological Monitoring of Plant Water Systems

Bioburden and Endotoxin testing is conducted on water collected from at least one sample point from the cold WFI loop each day, with each point of use tested at least weekly according to the schedule. All other grades/types of water are to be sampled and tested once per week.

Sterility Testing Procedure

Check if a product requires Bacterial Endotoxin testing and by which test method, either gel clot or KCA. If the product requires Bacterial Endotoxin testing, separate these samples from the sterility samples. Ensure that these samples are labeled with the product name & strength, batch, and code, and place these in the receptacle for the type of Endotoxin test required.

Determination of Heat Resistance of Spore Forming Organisms

If the spore-forming organism is an anaerobe subculture, it is onto a Trypticase Soy Agar (TSA) and Nutrient Agar (NA) or Sporulation Agar (SA) slope at 32°C (1.5°C) for 48 hours. If the spore-forming organism is an anaerobe, grow it on a Reinforced Clostridium Agar slope in an anaerobic jar at 32°C (1.5°C) for three days.

Identification of Microorganisms to Genus and Species Level

Bacteria requiring identification (ID) at least at the genus level include organisms isolated from the manufacturing environment, personnel, in-process and finished products, plant water, and other miscellaneous sources.

SOPs detailing the microbiological testing procedures for each sample will indicate the required ID level of recovered organisms. The following sections detail the procedures for the preliminary ID of microorganisms. Further ID at the species level is to be conducted for confirmation.

Micro Evaluation on Bioburden, Non-sterile, and Raw Materials

Non-sterile products and raw materials are tested to determine the presence of (Presence Test) and number of (Limit Test) microorganisms present. The type of organisms present may also need to be evaluated.

Some common pathogenic organisms must be absent (refer to Specifications). The potential pathogenicity of other Gram-negative rod organisms will be evaluated in the particular situation, and a maximum permissible level for other organisms is set.

Bacterial Endo Toxin Testing (LAL) – Gel Clot Method

The gel-clot method for bacterial endotoxin testing described in this SOP is based on the fact that Limulus Amoebocyte Lysate (LAL) will form a firm gel in the presence of bacterial endotoxin.

Bacterial Endo Toxin Testing kCA Method

The bacterial endotoxin used for KCA is a concentrated preparation of E. coli endotoxin. This preparation is not sterile and can potentially cause infection and fever.

Appropriate care should be taken when handling the freeze-dried powder and reconstituted solution.

Stock Suspension of Micro Organism

Stock suspensions of the noted microorganisms are used to perform monthly dilutions, which are used for growth promotion and stasis checks (See sections 6 and 7). Stock suspensions and dilutions must be placed in the refrigerator immediately after use for preservation. See Miclab-035 Aseptic Media Filling and Microbiology Integrity Leak Testing Procedure for Media Runs and Soup Tests requirements. Record the bacterial counts from the dilutions.

Sterile Sampling Procedure for Microbiology Laboratory

All sampling is the responsibility of the authorized persons in the appropriate sterile manufacturing teams. Production personnel are to deliver all Samples (except Personnel Monitoring), Settle plates (Fallout plates), and charts to the Micro. Lab. Sample Cabinets.

All delivered items must be logged into the appropriate logbooks. It is the responsibility of Micro. Laboratory staff will collect samples for testing, settle plates (Fallout plates) for incubation, and the charts for checking at least twice daily – once in the morning and again in the afternoon.

Gel Clot Validation Method

Preliminary Inhibition / Enhancement testing consists of running two (2) sets of product dilutions in parallel, one set containing the product alone and the other containing an endotoxin-spiked product. The concentration of the product decreases with increasing dilution while the concentration of the endotoxin remains the same. The endotoxin spike’s final concentration should equal twice the sensitivity of the Lysate used.

Laboratory Investigation for Atypical and OOS Results

This procedure applies to all microbiological testing used to support product release. This includes non-sterile and sterile in-process testing, finished product testing, and biological assays like endotoxin testing. This procedure also applies to water testing and disinfectant testing OOS results. Where confirmation of a valid OOS result leads to a more detailed investigation of the manufacturing process or environment, the laboratory investigation form (Form 690) should be attached to the report.

IPA Contamination Testing Procedure

A simple laboratory UV test can be done to check the consistency of the IPA. The test involves comparing the UV spectrum of the IPA sample with that of HPLC grade IPA from the Laboratory.

Control of Microbiology Test Methods

Reagents and Materials Required: List the major or unique materials needed for the test. This only needs to include standard microbiological items such as pipettes or loops if specific details are required that cannot be detailed in the General Test Method section.

Handling of Test Samples in Microbiology Laboratory
The Quality Control Microbiology Laboratory’s trained individuals are responsible for logging, handling, testing, and disposing of samples. The laboratory manager or designee reviews and approves MLT data. Controlled samples must be locked in the secure locker located within the Laboratory. The Team Leader maintains the locker key.

Documentation Requirement For Micro Test Method Validation

This procedure applies to Microbiology personnel responsible for validating or verifying microbiological test methods. The procedure outlines the requirements for approval of method development protocols, validation/verification protocols, and final validation summary reports.

Process, Cleaning and Methodology Validation Procedures

Concept and Procedure of Validation
Validation establishes a high degree of assurance that a specific process, activity, or system will consistently and reliably produce a product meeting predetermined specifications and quality characteristics.

The supporting evidence must be appropriately documented. Processes are considered “validated,” and the systems that perform the actions within the process are considered “qualified.”

Re-validation
Except for sterile/aseptic processes, process re-validation is NOT frequent as validated status is maintained via a change control process. The need for any re-validation outside of the change control process will be considered in response to repeated or unexplained batch failures or any adverse analytical trends.

Method Validation
Validation of an analytical or microbiological method is the process by which laboratory studies establish that the method’s performance characteristics meet the requirements for the intended analytical applications. Methods must be revalidated if conditions change significantly.

Cleaning Validation
Cleaning validation is a validation program to verify that the processes and procedures used to clean product residue from process equipment and components will consistently and significantly reduce the amount of active and excipient(s) and cleaning agent(s) to a concentration within calculated acceptance limits.

Validation of Laboratory Instruments
Laboratory instruments/equipment provide accurate and precise quantitative and qualitative analytical results for organic, inorganic, and biological products. The level of Validation/Calibration documentation required for each piece of equipment is assessed based on the testing methodology used, the instrument’s complexity, and the equipment’s analytical function.

Equipment Specification and Qualification
This procedure ensures that process equipment and systems are developed and supplied per Good Engineering Practice (GEP). GEP recommends that:

– Equipment should be built in accordance with plans and specifications, approved or authorized by the appropriate individuals

– Equipment should be inspected, tested, and documented by qualified individuals

– A minimum level of documentation should be provided for all systems and equipment

– Documentation should cover the design, fabrication, construction, inspection, and commissioning phases.

In-House Trial
This SOP defines the procedures for conducting in-house stand-alone trials on systems, processes, and equipment. The purpose of a trial may be to fine-tune our process methods, evaluate new equipment, products, components, and systems, and evaluate changes to existing equipment (including new machine settings). There can be an overlap between a trial and validation in that Trial documentation may form part of a latter process validation (i.e., concurrent and prospective validation) and qualifications (OQ, PQ).

Computerized Systems Validation
Computerized Systems cover a broad range of systems, including automated manufacturing equipment, control systems, automated laboratory systems, manufacturing execution systems, and computers running laboratory, manufacturing, or distribution database systems.

A computerized system consists of hardware, software, and any network connections, together with the controlled function and the associated documentation that performs a certain function. The computer is just one part of the process.

Impact Assessment for Computerized Systems
Impact Assessment is the process by which Computerized System Items are identified and evaluated. Impact Assessment will guide the level of validation required for the task.

All validation requirements will be detailed or attached to the Validation Plan or Change Request forms and approved by the validation or change request committee, respectively.

Functional Testing Guide for Computerized System
SOP ‘VAL-040 Computerised Systems Validation‘ overviews the computerized systems testing philosophy. Systems are categorized in line with GAMP principles, and their functions are listed and rated for GxP impact in Impact Assessment forms, per SOP ‘VAL-045 Impact Assessment for Computerised Systems‘.

The level of functional testing applicable to each function within the computerized system is rated as “Minimal,” “Some,” or “Extensive.” All levels aim to verify that the system functions correctly (performs as specified in normal situations). In contrast, the increased levels also emphasize verification that the system does not function incorrectly (does not malfunction when challenged with unusual circumstances). The selection of tests also considers the Risk Assessment process, per SOP VAL-055 ‘Design Qualification Guidelines.’

Design Qualification Guidelines
Compliance with both cGMP and suitability of use should be documented. DQ integrates the URS and FS and relevant design documents, e.g., design specifications, to ensure that what has been designed will meet regulatory and internal requirements.

The underlying theme of assuring design compliance before the construction or manufacture of the facility, system, or equipment is inherently logical and avoids costly errors in judgment.

Protecting the Reliability of Electronic GMP Records
Audit Trail is data and record in the form of a logical path linking a sequence of events used to trace the transactions that have affected the contents of a record. It will usually contain all original data, the author of the changes, the time and date, and the reason for that change.

The audit trail is not the same as an operating system activity log; it is generated at the application level and logs actions performed to a specific electronic record. The audit trail should also be immutably integrated with the actual record.

Cleaning, Derouging, and Passivation of the Stainless Steel Parts of the Purified Water System
This SOP defines the procedure for cleaning, passivating, and deranging the purified water system at a GMP site. The procedure may be performed after construction, invasive repair, or maintenance.

The various parts of this procedure are to be performed as necessary. Parts of this procedure may not always be executed simultaneously (e.g., the storage tank for the purified water may be cleaned and passivated without cleaning and passivating the ring main).

Cleaning Validation Analytical Methods
Validation of cleaning validation analytical methods involves validation of both the sampling (generally swab or rinse) method and the analytical test method.

Validation of the sampling procedure demonstrates that the residue of interest can be recovered by the sampling method at the required level. Validation of the analytical test method demonstrates that the residue recovered by the swab from the equipment surface can be reported at the levels at which it was present on the equipment.

Validation Deviation Management

Validation studies include process validation (including raw material evaluations), cleaning validation, equipment qualification, computer validation, facility & utility validation, analytical method validation, and method transfers. This procedure does not apply to deviations raised outside of an approved validation study.

Validation Master Plan

The design and operation of a GMP facility must embrace GMP considerations, as defined by the applicable regulations, for the manufacture of finished pharmaceuticals, applicable industry standards, corporate quality standards and guidelines, and environmental, health, and safety requirements.

Process Validation Guideline
Introduction of new products or significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process, should be validated.

The Validation Committee (VC) will assess the need for and execute process validation, as per the policy requirements set out in this SOP.

Equipment Validation Guideline
This validation guideline will apply to all manufacturing, packaging, and laboratory equipment at the GMP manufacturing facility. That is, all equipment could directly or indirectly affect the quality of the products.

This guideline does not include computer validation, except those used to directly control an item of equipment. Any system for which proper operation can be fully assured through routine calibration and preventative maintenance programs does not require validation and is not within the scope of this document.

Facility and Utility Validation Guideline
Installation qualification (IQ) and Operational Qualification (OQ) exercises assure, through appropriate performance tests, related documentation, and records, that facilities and utilities have been commissioned correctly and that they will be reliable and within prescribed or specified operating limits.

Process Validation Sampling
Appropriate sampling plans in the manufacturing instructions or validation protocol will support all sampling. Sampling will follow the general principles outlined below.

Raw Material Evaluation Process
This procedure covers changes to an active pharmaceutical ingredient or excipient, including changes to the manufacturing site and/or manufacturing process. An evaluation must be conducted to demonstrate that the change will have no impact on finished products or processes.

Computer Systems Validation Guideline
Computer systems validation (CSV) guideline includes all new and legacy computerized systems that affect regulatory compliance practices (i.e., manufacturing, packaging, testing, storage, and distribution of site products shall be validated.

GMP Manufacturing facilities incorporate computer and computerized systems at all levels, from local Programmable Logic Controllers (PLCs) controlling manufacturing and laboratory equipment to high-level stand-alone systems. This guideline applies to the validation of all new and legacy systems.

Process Validation for Liquid and Solid Dosage Manufacturing
The validation protocol is a written plan stating exactly how the validation study will be conducted. The protocol generally explains what will be done to validate the specific process, how it will be executed, who will execute it, and what the acceptance criteria are.

Any deficiencies in the prerequisites detailed above must be resolved before proceeding with protocol execution or a justification documented in the protocol, which will be approved by, at minimum, the Validation Manager, Quality Assurance Manager, and the Process Owner or their delegates by approving the protocol for execution.

Cleaning Validation Guideline
Cleaning procedures are established to reduce cross-contamination between products, cleaning agents, and microbial contamination to acceptable levels. The cleaning and sanitation procedure define the frequency of cleaning, the cleaning method, the type and concentration of cleaning agents used, or the automatic cycles employed for Cleaning In Process (CIP) systems.

Guideline for the development of a Validation Project Plan
The Validation Project Plan (VPP) is a dynamic document that provides the framework and strategy that may require updating over the project’s life cycle and also ensures the computer system is validated throughout the system’s life cycle.

It defines the activities, responsibilities, and deliverables required to provide documented evidence that a computerized system (in-house developed or purchased) does what it purports to do (according to specifications) and will continue to do so in the future.

Guideline for The Development of A Computer Validation Project Plan
The VPP provides the framework and strategy for ensuring the computer system’s validation throughout its life cycle.

Risk Assessment for Computer Validation Systems
The Risk Assessment process addresses the following questions:

– Does this computerized system require validation?

– How much validation is required for this system?

– What aspects of the system or process are critical to product and patient safety?

– What aspects of the system or process are critical to business?

It is impractical to completely test every aspect of a computerized system; therefore, the effort should be focused on critical areas.

Development of a User and Functional Requirement Specification
The purpose of this document is to clearly and precisely determine what the user wants the system to do, define what a system should do, and provide which functions and facilities based on the URS requirements.

Development of A Functional Requirement Specification for Computer Systems
This procedure will be used as a guideline for developing a Functional Requirement Specification document for a computer system at the GMP manufacturing facility.

Conducting an Electronic Record and Signature Assessment
The assessment worksheet must be completed for the following:

– Records and signatures that are required by the FDA that are created, modified, maintained, archived, retrieved, or transmitted in electronic form

– Records and signatures that may be submitted to the FDA in electronic form, whether required by FDA regulation or not

– Signatures are applied electronically to FDA-required records or records that may be submitted to the FDA, even if the signatures are not required by FDA regulation.

Handling of Material Used for Trials
All materials used in trials must be kept separate from production materials. When finished, the trial material must be stored in Quarantine Hold or the reject area and must not enter the pharmacy store with passed status material—responsibility for Validation / Technical Services, Quality Assurance, or Manufacturing.

Periodic Review of Systems and Processes
This SOP covers the periodic review of systems and processes such as validated direct impact systems (including the facilities, utilities, equipment, process control systems, and computer/automation systems) and Processes in the production, storage, and distribution of drug products in a GMP site.

Packaging Trials
Because it is so easy to overlook secondary criteria beyond the immediate qualities being examined by the trial, communication with the management group and all stakeholders is essential to explore further potential and impact, which may be revealed by other tests within that trial.

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GMP | Manufacturing and Packaging Procedures

Clothing Requirements
NO eating or storing of food will take place inside the factory area. (This includes lollies and chewing gum). Drinking water is supplied in some areas of the factory. (The water must only be consumed at the water cooler, and the cup must be placed into the rubbish provided.) No other drink is allowed.

Cleaning Responsibilities and Methods
Cleaning aims to prevent product contamination by foreign materials from another batch or by dirty parts which may contain bacteria. It also removes debris, which may interfere with the smooth operation of machines. It is the responsibility of all Manufacturing Staff to follow this SOP.

Factory Cleaning
The rules and GMP requirements apply equally to Contract Cleaners and Operations staff. All cleaners should undergo Induction conducted at the Site and be supervised while working in the Plant.

Manufacturing Pest Control
By the nature of their work, Pest Control Contractors need to use toxic materials to control the various forms of vermin sometimes found in our Plant. The nature of our work makes it imperative that there is no chance of contamination of our products. It is, therefore, necessary to closely define the materials used, the locations where they are to be used, and how they are used.

Production Logbook
This procedure outlines the generation, maintenance, and filing of Production logbooks. Production logbooks form part of the documentation system required by the Code of GMP to provide complete and up-to-date histories of all batches of products. The logbook provides a key link in the process of traceability.

Packaging Configuration for Production Line
This SOP provides an alphabetically indexed diagram of shipper packing and pallet packing configurations for any packaging process. This procedure contains schematic diagrams of different packaging configurations and calculations of the total unit to be packed per container, which can be used in your packing lines.

Checking of Components Before Use
Check the Material Code and Lab. Batch No. physically for each component on the Site label. Ensure every item is present at the beginning of the process or received later. (See SOP MAN-055 ‘Procedures for Line Clearance, Line Opening and Line Cleaning‘ for the line opening procedure).

Tag Out Procedure
This SOP describes how to prevent the risk of personal injury or damage to equipment likely to be caused by operating or attempting to operate machinery or equipment diagnosed as being unsafe, in need of repair or maintenance, or formally removed from service.

The SOP covers all isolation, condemning, repair, or maintenance work that necessitates a device or machine to be taken out of service. This SOP applies to any situation where energy (either supplied to equipment or stored within it) needs to be isolated to ensure the safety of any person working on or near equipment, processes, or services – for any reason whatsoever.

Line Clearance, Line Opening, and Line Cleaning
Line Clearance: A check is performed before an operation to ensure the Line/Machine is free of ANY product, components, and documentation. This is the first step in a process, which is to be done before a Line Opening.

Reconciliation of Component and Product
The purpose of reconciliation is to ensure that all materials have been accounted for and no mix-up occurred. Reconciliation is done on printed and/or coded components and the finished product. The limits outlined in this procedure should help detect errors at the time of manufacture and avoid the release of a non-conforming product.

Construction, Operation, and Cleaning of Tablet Packing Machine
This procedure describes the machine construction and operation, machine start-up and cleaning of a typical tablet Blistering machine, and the Cartoner for tablet packing. You will be able to create a new procedure for your packing line based on the format of this SOP.

Manufacturing Instruction for Packing
This procedure describes how to create complete manufacturing instructions for your process line to be followed by your manufacturing employees. To make the instruction more practical and easy to understand, a sample instruction is added as a protocol for a typical tablet packing process. All the related blank forms are attached at the end of the procedure for a better understanding.

Mop Cleaning
There are four different coloured mops used at the site in the cleaning process. The Cleaners choose to use colour-coded mops to reflect the factory’s environmentally graded areas. These mops, when soiled, are collected from the various cleaners’ rooms throughout the site and taken to the laundry for washing and sanitising. They are then returned to the cleaners’ rooms and sorted for reuse.

Scheduling of Production Lines
This procedure describes how to produce a monthly manufacturing schedule following an agreed 12-month plan to provide a sequence of work that will enable the scheduling of support groups (i.e. Quality, Technical, and Warehousing), incorporate any planned engineering downtime (i.e. project work, calibration and preventative maintenance), create and release batches according to the agreed weekly schedule, provide key dates for product supply to support Customer Service.

Vacuum Leak Testing Procedure
This SOP describes the setup and operation of a standard vacuum Leak Tester for the popular vacuum leak testing used in a typical packing line.

Tablet Packing – Start-up and In-process Testing
This SOP explains the procedure for all start-up and in-process tests required to be conducted by production operators in the tablet areas. You will not use all of these tests for a batch. The manufacturing instruction (MI) sheet will guide you through what needs to be done for a batch.

Finished Product Sampling for Testing
This procedure describes the process of sampling manufactured finished goods required to be taken by production personnel for laboratory testing. A typical tablet packing process is used here as an example.

Returning Components from Packaging Floor
This procedure defines how to return all surplus packaging components to the Warehouse on completion of a Packaging lot. SOP for Reconciliation of Packaging Components details the procedure to be followed for Finished Goods, Samples, and Reject Material.

Warehouse Management Procedures

Receipt of Incoming Goods
Check that the goods being received are numerically equal to those mentioned on the Incoming Invoice and are of the same type, e.g. cartons, drums, rolls, etc. Check that descriptions on the containers, where they are marked, match with those on the Incoming Invoice

Incoming Raw Material and Components Handling
The procedures covered in this SOP are the responsibility of the Samplers. The raw material used in this procedure includes Actives, Excipients, Imported finished goods (i.e., Tablets), chemicals, and packaging components.

Processing Issues Return and Rejects
This SOP contains step-by-step instructions on the issue of tested and QC-released components for batch production, as well as documentation needed to capture identification and traceability information during the picking, assembling, and transferring those components from warehouse to production. This procedure also has instructions to follow during the return and reject processing of raw materials and components from production to warehouse.

Dispatch of Goods from Warehouse
The Warehouse receives a Finished Goods Shipping Form (Form – 550 – Finished Goods Shipping Form) from the distribution team, which indicates (in Part A) the Date to be shipped, Finished Goods Code, Shipping Number, Product Description, BPN numbers, number of pallets, GBS number, pallets location in Quarantine, invoice number, Total quantity, Address to be sent and Transportation mode.

Warehouse Inventory Management
All warehouse storage locations and storage bins are counted, except nominal locations. Nominal locations are interim or transfer locations only where stock is not located physically.

Warehouse Locations and Storage Area
To understand and draw a schematic diagram of Warehouse and Production areas, identifying incoming goods storage unit types and storage bin types, Quarantine, Reject Cage, Cool room, Flammable storage, Dispensary booths, Production area, finished goods quarantine area, and finished goods storage areas. To define how storage unit types and storage bins are numbered.

Finished Goods Transfers to areas
This simple SOP contains instructions and documentation on the movement of finished goods from production to warehouse finished goods quarantine location until the samples are tested and released by the authorised persons.

A sampling of Raw Materials
Sampling of Raw Materials represents a substantial contamination risk. The Sampler must make every effort to ensure that the sampled material is not contaminated by the sampling environment, including cross-contamination from other raw materials and microbial contamination.

Sampling of Components and Printed Materials
Sampling of components and printed material represents a substantial contamination risk. The Sampler must make every effort to ensure that the material is not contaminated by the sampling environment, including cross-contamination from other components and printed material.

Work in Progress
This simple procedure describes the construction and locations of different work-in-progress areas between production and warehouse for temporary storage of raw materials, components and finished goods.

Warehouse Racking
This SOP outlines the measures to ensure the safety of all goods and personnel when using the storage racking system to avoid injury to staff or damage to property. This procedure is concerned with handling and storing materials or products and reporting any damage that may occur. This SOP particularly relates to the activities of the receiving and distribution warehouse staff.

Forklift Operation in Warehouse
This SOP gives instructions on operation requirements and maintenance of forklifts used in the warehouse, as well as safety precautions to be taken during the operation of forklifts under load.

Dispensary Procedure
This procedure mainly concerns dispensing techniques, plans, and instructions for released raw materials for production use. An example of a tablet dispensary procedure is prepared for better explanation and understanding of dispensing. So that you know, you will be able to follow the instructions for dispensing any raw materials in your facility.

Material Purchasing Information Record
This simple procedure describes how to keep purchasing information for approved materials, vendors, manufacturers, standard and current pricing, and third-party agreements.

Generation of Purchase Order
This procedure describes the steps to be followed by the planning and procurement department to create purchase orders for inventory items to be purchased from overseas and local suppliers.

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Validation Guidance

Validation of Analytical Test Methods
This guideline provides guidance for the validation of analytical test methods. These analytical test methods include those tests that evaluate API, Raw Materials, In-Process samples (e.g. reaction monitoring), and early intermediate materials (before introducing the first critical intermediate). This includes risk assessment and prioritization, system suitability, precision and accuracy, quantity and detection limit, linearity, range and specificity, robustness, etc.

Calculations of Residue Limits for Drug Products for Equipment Cleaning
The Maximum Allowable Residue for Therapeutics (MART) and Residue Acceptability Limit for Therapeutic Dose (RALT) should be calculated based on each product that is to be processed in a specific equipment train and determined by the formulas and equations provided in Appendix A. A common default MART is not more than ten (10) ppm.

The calculated MART and the default MART should be compared, and the lower of the two (2) should be used. A Toxicity limit may also be calculated and compared to the default MART, the NMT 10 ppm, and the lower of the three limits chosen.

Swab Sampling for API Equipment
The cleaning evaluation determines the major contaminant(s) to be sampled and tested for each equipment item. The table on the following pages provides guidance for each equipment type.

The table provided below is intended as guidance and does not substitute a thorough consideration of the design of equipment to identify those locations deemed challenging to clean, nor does it mandate the inspection or sampling of suggested locations that would require vessel entry or undue safety concerns based upon the design, size, or intended use of equipment.

Consideration of locations to sample can be documented as part of the cleaning evaluation documentation (e.g. site SOP ) conducted to develop a sampling plan of the equipment system.

Product and Equipment Grouping and Worst-Case Product Selection
The primary objective of grouping related items in validation is to be able to identify a ‘worst case’ or representative item that allows the results of a particular validation exercise using that item to be applied to the remainder of the items in that group. In doing so, the overall burden of validation is reduced while objective evidence that supports the validation of grouped products or equipment is obtained.

Validation of Test Method for Rinsate and Swab Sample
The area to be swabbed must be defined; typical areas range from 5cm x 5cm to 4” x 4”. It shall include special requirements and/or calculations for specific areas or equipment. It should be constant and well-defined at each site to ensure consistency. This may be a standard area, as defined by site procedure (and executed using a template), or maybe a specific area for that piece of equipment. The actual area to be swabbed may be defined in the validation protocol.

Visual Inspection and Quantitation in Equipment Cleaning
Depending upon the desired outcome of the equipment cleaning activity, the visual inspection can take on different emphasis to achieve the desired goals. Visual inspection will be a part of all cleaning procedures developed, and as such, each site should define the significant operations, responsibilities, and expected results within site SOPs or individual cleaning instructions.

Cleaning Evaluation Documentation and Records for Cleaning Activities
To appropriately document the development of the cleaning requirements for a material and/or equipment train, it is recommended that a cleaning evaluation report be prepared. This may be a single report or several reports; there is no requirement for a document to be titled “Cleaning Evaluation Report’. This may be fulfilled by documenting the evaluation within a separate report, the site cleaning validation master plan, validation project plan, or validation protocol as appropriate for the site.

Critical Process Parameters for Drug Product
Critical quality attributes (CQA) are defined as physical, chemical, or microbiological properties or characteristics of a material (drug product or API) that directly or indirectly impact that material’s safety, identity, strength, purity, or marketability.

Identification of the Critical Steps for the Drug Manufacturing Process
A “step”, in the context of this guidance, may be a single manufacturing instruction or a series of instructions that constitute a unit operation. Typical unit operations in manufacturing tablets (a common solid dosage form) include but are not limited to weighing, sieving, mixing, granulating, drying, milling, tableting, coating, and printing.

Process Validation for Drug Products and Medical Devices
The Normal Operating Range (NOR) should be within or equal to the PAR. A documented Risk Assessment, such as comparing the margin between the NOR and the PAR, Process Capability analysis, or statistical evaluation, may be used to determine the critical parameters.

Equipment Cleaning Validation for API
A Cleaning Evaluation should be conducted, documented, and approved by the Site Quality Authority and Production Team. This evaluation may be a single report or several reports, may be equipment-centric or process-centric, and may document or reference the required information. The purpose of this documentation is to justify the decisions made in developing the cleaning validation for Active Pharmaceutical Ingredient protocols. This evaluation should determine or consider each equipment unit.

Equivalence Criteria of Impurities in API Process Validation
The registered specifications may or may not accurately reflect the most recent historical data for older processes. In cases where the specifications may not reflect more recent historical data, it is recommended that additional criteria, such as meeting the upper statistical limit of historical data, be considered for validation equivalence criteria.

Equivalency Comparison of Drug Product
It is recommended that determining equivalence criteria includes considering the number of reference batches available, the statistical distribution, and the confidence that data are representative of the process.

Calculation of Clean Equipment Hold Times (CEHT)
The decision to determine if CEHT must be specified and/or validated is based on a risk assessment that includes the nature and use of the product and the conditions under which the clean equipment is held. Whether to specify a hold time, the amount of data that may be needed, and whether to conduct a clean equipment study is dependent on the risk assessment.

Evaluation of Uncleaned Equipment Hold Time
The uncleaned equipment hold time period is defined from the “end of manufacturing” to the start of cleaning. The end of manufacturing is when the individual equipment piece is emptied of the material contained within (e.g. when no additional product is removed for further processing).

Potential Impact of Changes in Process Validation
Evaluating proposed changes to a process shall include a documented assessment of the validation impact of proposed changes. Where appropriate, I would recommend using a risk assessment in the evaluation of proposed changes.

Process Validation Sampling
Sampling plans and methods shall be predetermined and documented (for example, in a SOP or validation protocol). Sites should be able to provide a scientifically sound rationale for the sampling and testing plan. The sampling plan should identify (where appropriate).

Determination of Swab & Visual Inspection Sampling Locations
The cleaning evaluation determines the major contaminant(s) to be sampled and tested and the sampling locations for each equipment item. Table I below provides guidance for sampling locations for each equipment type. This table does not substitute for a thorough consideration of the design of equipment to identify those locations deemed most difficult to clean, nor does it mandate the inspection or sampling of suggested locations that would require vessel entry or require undue safety concerns based upon the design, size, or intended use of equipment.

In – Process and Bulk Drug Product Holding Times
Although there are no specific regulations or guidance documents on bulk product holding times, good manufacturing practice dictates that holding times should be validated to ensure that in-process and bulk products can be held, pending the next processing step, without any adverse effect on the quality of the material. This practice is supported by indirect references made to determining holding times in various FDA guidance documents and FDA regulations.

Demonstration of Active Pharmaceutical Ingredient (API) Batch Homogeneity
Homogeneity is the acceptable distribution of chemical and physical properties within a batch based on predefined criteria. The intent of examining homogeneity during the validation is to demonstrate that the quality of a sample collected from any location within a batch represents the quality of the entire batch.

Continuous Quality Verification
This guidance provides an example of key information to include in the documentation that contributes to the overall CQV package. Documentation for a process may include some or all of the content described here, depending on the nature of the process. Other documentation may also be needed to support a CQV approach. No particular format has been defined for documenting this information, and the necessary information may appear in a single report or multiple reports.

Supporting Documentation for Continuous Quality Verification
The CQV approach to process validation may be applied to new and legacy processes when the necessary information is available. It requires a good understanding of the process and a process control strategy that ensures repeatable and robust performance of the process.

Dose & Toxicity Data for Cleaning Limit Calculation
For consistency, the use of Acute Oral LD50 values obtained using rats as the study population is recommended to be used. The justification for using acute oral LD50 values for rats is based on a commonly referenced article. Layton et al suggest that a safety factor to be used in calculating the Acceptable Daily Intake (ADI) be in the range of 1×10 – 3 to 5 x 10 – 6. This factor is based on small mammal and oral rat data.

Inspection Attributes in Non-Sterile Packaging Validation
General criteria for inspection and control of defects are described in Appendix 1. Three classifications, critical, major, and minor, are used to classify packaging defects. The Tables below on defects and attributes can be used as a starting point for those new to defect classification during packaging validation.

Laboratory Instrument Qualification
Documentation of Qualification Activities Performed at the Site by a Vendor (e.g., protocols and results) should be obtained, reviewed, and approved by the Quality Authority.

Matrices and Bracketing in Process Validation
Bracketing assesses a single parameter or variable by identifying the edge(s) of the range of conditions for the parameter or variable and assessing these during validation to span the possible range of that parameter/variable. Bracketing can be applied to process parameters, multiple pieces of identical equipment, and/or different size considerations for the same product.

Considerations for Selecting Packaging Lot Sizes During Packaging
One of the industry standards in packaging validation indicates that: “A packaging validation lot must be representative of the typical packaging process and be of sufficient length such that packaging validation lot will exhibit normal packaging process variability”. In addition, a packaging validation run (e.g., an entire lot or defined portion of a lot) shall be determined by the Validation Committee based on a technical evaluation and experience with the packaging process.

Non-sterile Active Pharmaceutical Ingredient (API) Manufacturing Area
For each API product, a risk-based assessment of environmental control requirements should be performed, documented, and approved by the Site Quality and Production Teams. The risk assessment may be conducted on a product or facility-centric basis. This risk assessment should include consideration of at least the following:

Potential Critical Process Parameters and Validation Practices
Drug products come in a variety of packaged forms, frequently packaged with common steps and equipment. The potential critical process parameters are often the same from process to process, and this guidance captures these common CPPs and CQAs. The specific practices regarding packaging process validation are described as well.

Process Validation Sampling for Non-Sterile Liquid Semi-Solid Drug Products
Sampling of solutions poses few special concerns as all materials are in solution, and each sample is the same as every other sample if homogeneous. For solutions, the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved and that the solution has been adequately mixed.

Process Validation Sampling for Non-Sterile Solid Dose Drug Products
The Product Quality Research Institute (PQRI) Blend Uniformity Group has developed an approach to demonstrating blend uniformity by combining blend testing with in-process dosage unit compendial testing. This approach postulates that the analysis of finished tablets/capsules can support or provide statistical evidence that a failing blend result was due to poor sampling or handling technique.

Performance Qualification Versus Process Validation
In preparation for process validation, the limits of the Normal Operating Range (NOR) of critical parameters are recommended to be supported with data to demonstrate reproducibility and robustness. Reproducibility is the ability of a process to consistently produce the same product that meets its Critical Quality Attributes (CQAs).

Periodic Review of Processes and Systems
Validated processes and qualified systems (from this point forward, referring to equipment & computer systems) must be periodically evaluated to verify that they remain in a validated state. High-risk processes (e.g. sterile or aseptic) may also require routine re-qualification and/or re-validation.

Release of Drug Product and API pre-validation and Validation Batches For Commercial Use
Batches of product manufactured before completion of PV activities may be released for commercial use following verification of acceptable results for all tests, verification that the acceptance criteria have been satisfied, and the critical process parameters, ranges, and materials used are the same as the proposed commercial manufacturing process and fulfilment of other site requirements for product release as necessary.

Selection of Critical Process Parameters for Validation
A CPP is “a process parameter whose variability impacts a Critical Quality Attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality.” Identifying the CPPs for a new process is essential to defining the process control strategy.

Critical Process Parameters for Semi-Solid Dosage Forms
The most common presentations of semi-solid dosage formulations are therapeutic creams, ointments, gels, lotions, emulsions, salves, pastes, and other forms of similar viscous consistency. Topical and ophthalmic are the primary routes of administration for semisolids. Semisolid drug products, depending on their use, can be sterile or nonsterile. Requirements of process validation that are specific to semisolid drug products are stated in another guidance.

Potential Critical Process Parameters Solid Oral Dosage Forms
Critical process parameters (CPPs) and critical quality attributes (CQAs) that need to be monitored during process validation for a bulk solid oral dosage formulation depend on its presentation (e.g. compressed tablet, coated tablet, capsule) and its drug release characteristics (immediate release – IR or modified release – MR ).

Solvent Recovery Validation Example
This guidance provides an example of the contents that may be found in solvent recovery validation documentation, including appropriate acceptance criteria for solvent recovery validation. The processing addressed by this type of validation includes the recovery of the used solvent to provide an acceptable solvent.

Test Deviations During Validation
Deviations that occur during validation testing must be documented and investigated in accordance with site procedures. Additionally, a summary of all deviations, investigations, or corrective actions associated with a specific validation activity must be included, discussed and cross-referenced in the validation report.

Validation Activities During Technology Transfers
While overall Technology transfers often include many aspects (e.g. validation, stability, regulatory, and safety considerations), this guidance focuses on the validation aspects of technology transfers. Qualification and validation requirements for processes, cleaning, analytical methods, and systems (equipment, facilities, utilities, etc.) should be documented in Site Quality Standards.

Validation Considerations for Rework and Re-process of Active Pharmaceutical Ingredients
Compliance with regulatory filings, consideration of impact on product stability, and deviation investigation activities should be evaluated but are outside this guidance’s scope. For more information regarding regulatory filing compliance, stability, and deviation investigation, please review the relevant guidance.

Validation Documentation
The documentation should be based on the scope of the site or Center function’s operations and/or functional areas. The program/strategy documentation may reference other documents addressing various aspects of validation, for example, different facilities within a site or different validation types.

Shipping Validation for Biopharmaceutical Materials
The quality of biopharmaceutical materials can be protected during shipping through well-considered planning, selection of appropriate protective packaging, and qualification testing conducted at worst-case conditions.

System Level Impact Assessment for Information Systems
Systems Validation, all new systems shall be considered to be ‘direct impact’ systems unless there is documented rationale based on a System Level Impact Assessment (SLIA) for classifying systems as either “indirect impact” systems or “no impact” systems, based on the system’s potential to impact product quality or regulatory compliance – practices.

Clean Pure Steam System Commissioning, Qualification, and Sampling Plans
This guidance defines the sampling location, frequency, and testing activities, utilising a risk-based approach for supporting the commissioning and qualification for a clean/pure steam system. The recommended practices are derived from the latest ISPE Good Practices Guide edition, “ Commissioning and Qualification of Pharmaceutical Water and Steam Systems”.

Quality Management Guidance

Product Quality Complaint Handling
Any possible failure of a drug product to meet any of its specifications. Quality complaints may be of a routine nature or may be determined to be a potentially serious quality complaint allegation and will be classified as an Expedited Complaint to accelerate the complaint investigation and submission to the appropriate regulatory agencies and/or competent authorities, if necessary.

Application of Quality Risk Management to Periodic Review of SOPs
This guidance document strictly applies to documents classified as Standard Operating Procedures (SOPs), written as instruction-type documents describing how a requirement is to be followed or an act is to be executed.

Statistical Rationale for Raw Material Sampling
The Military Standard plans (e.g., ANSI/ASQC Z – 1.4, ISO 2859 – 1, & BS – 6001 – 1 are all one & the same and conform to MIL-STD 105E) are widely accepted as statistically based sampling plans. This guidance document will show that √N+1 sampling plans offer similar protection as Military Standard plans with specified AQL levels between 1.0 and 1.5 (2.5 for the 16 to 25 lot size) per cent for small lot sizes up to 150 units. In these cases, the two sampling plan approaches can be used interchangeably with similar risks to lot acceptability decisions and outgoing quality.

Quality Risk Management Application for Critical Instrument Calibration
Calibration frequencies for critical instruments may be adjusted as necessary based on calibration data or other information that may support a change. Before extending calibration intervals, review the calibration history of the instrument based on the table below. Consider the results of the calibrations [e.g., Return to Service (RTS) limit exceeded, etc.] in the listed time window when modifying frequency.

Structured On-the-Job Training System
This document will cover the various aspects of a Structured On-the-Job Training (SOJT) system, including determining when SOJT is appropriate, components of the system, components/steps in the system, and the required documentation.

Training system for Aseptic and Preparation for Aseptic Operators and Support Staff
This guidance is targeted at individuals who design, review, approve, and use training systems, training effectiveness assessments, and training materials for the qualification of aseptic operations personnel.

Disposal of Rejected and Waste Materials
Rejected and Waste Materials, Before 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:

Quality Assurance Audit
The Site Quality Team should prepare and maintain a master list of site operations that may be subjects of the QASA program. Collectively, that list should cover all major regulatory-related operations at the Site. Illustrative examples for production Sites include, but are not limited to, the following.

Annual Product Records Review
Data from Production Batches/Lots of all APIs and Marketed Drug Products, including Quarantined – HOLD and Rejected batches/lots, should be summarised annually. The criteria for identifying the first and last batch in the review period should be defined in Site procedures [e.g., Manufacture Date, Quality Control (QC) testing date, final disposition].

Receipt, Approval, and Use of Labels and Labeling
Rooms or Areas, Lines, and Equipment used for packaging and labelling operations should be thoroughly inspected and purged of all documents, labels, and labelling from the previous run if not required for subsequent operation, following procedures approved by the Site Quality Team and the Site Production Team.

Weighing and Measuring Practices in Manufacturing Operations
Methods for Measuring or Calculating Volumes of Liquids in Tanks include, but are not limited to, the following:

– Use of a clean and accurately calibrated stainless steel rod or ruler or a sight glass to measure the height of the liquid in the tank;

– Use of a calibrated flow meter or

– Use of calibrated weigh cells on load cells on the tanks.

Material Supplier Approval
Approval of a New Supplier, New Materials from an Already Approved Supplier, or a New Supplier Manufacturing Site, actions to be taken, include and are not limited to, the following:

– Assess the need for a Supplier Audit using risk assessment methodology;

– Conduct full raw material testing of at least three representative raw material lots;

– Conduct pilot laboratory use testing;

– Perform plant trials;

– Evaluate Packaging Materials; and

– Evaluate product stability.

Storage & Distribution of Drug Products and Medical Devices
Warehouse Storage should provide sufficient cleaning/inspection space behind pallets or racks. If the warehouse storage area is insufficient for cleaning and inspection, materials should be moved so floors behind stored materials can be cleaned as needed, but at least once every three (3) months.

Control of Manufacturing and Packaging Defects Non-Sterile
Inspection Requirements for each type of product, container/closure configuration, and packaging configuration should be written and approved by the Site Quality Team and include and not be limited to the following information:

– Determination of the minimum number of product units that must be sampled and the frequency of inspection; and

– Identification of physical attributes that are considered defects and their respective Acceptable Quality Limit (AQLs).

Pest Control
Each Site Pest Control Program should be supervised by a qualified Site Pest Control Coordinator who should ensure that the program is coordinated among departments, the Site Quality Team, and any contracted pest control service employees allowed on the Site.

Receipt and Storage of Raw Materials and Packaging Materials
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 a label containing the site’s in-house material code is applied by the supplier, the label should also be verified during or immediately after unloading.

Sampling of Production Materials and Finished Goods
Sampling SOPs should include, and are not limited to, the following information:

– Sampling method;

– Sampler apparel;

– Sampling tools, utensils, and equipment to be used;

– Amount of the sample to be taken;

– Instructions for any required sub-division or compositing of the sample;

– Type and condition (e.g., sterile or endotoxin-free) of the sample container to be used;

– Identification of containers sampled;

– Sample identification;

– Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;

– Special storage conditions; and

– Instructions for cleaning and storing sampling equipment if disposable sampling equipment is unused.

Water Purification, Storage, and Distribution for Pharmaceutical Production
Potable Water may be used in the final steps in manufacturing APIs for use in nonsterile drug products if the Site Quality Team has approved a documented rationale justifying the continued use of potable water. Such documented rationale should include, but not be limited to, information which demonstrates that:

Use of a Risk-Based Approach To Establish External Quality Assurance Audit Frequency
The Site Quality Team shall be responsible for the following audit-related activities:

– Review and issue Supplier Audit prioritisation and schedules

– Conduct Supplier Audit.

Reduced Testing Program
There is limited value in testing starting materials, intermediates, APIs, excipients, and packaging components previously released from vendors or other sites whose operations are in a state of compliance with cGMPs and where the materials have reliably supported the production/supply of goods that meet the site’s in – house specifications.

GMP Training System
Introduction to the GMP Training System should be part of any colleague’s orientation to the site and should be the structure upon which all the GMP training needs of the colleague are met. This document will cover the various aspects of the system, including job function curriculum, training record system, GMP orientation, SOP training, GMP concept training, structured on-the-job training, and training effectiveness assessments.

Stability Testing
Stability Testing for Finished APIs (including API Intermediates for Sale) and Drug Products is required for, but is not limited to, the following situations unless there is documented rationale approved by the Site Quality Authority for not performing stability testing:

Quality Risk Management application to identify Deviations vs. Events
This document provides guidance on two approaches to assessing the risks of identifying deviations vs. events.

Implementation of Real Time Release
This document provides a framework for RTR projects. It outlines the important components that must be considered in any RTR program. It provides guidance on developing an underlying control strategy that will enable the adoption of an approach to release that relies on process understanding, monitoring, and control rather than end-product testing.

Preventive Maintenance
The PM Program should include or reference the following:

– List of all systems and associated components that require PM;

– Definition of responsibilities for PM requirements and activities, including on-site contractors and vendors;

– Management of off-site contractors and vendors performing PM activities (e.g., Quality Agreements, vendor audits, and vendor assessments);

– Method for establishing and managing PM frequency;

– Method for establishing and documenting acceptance criteria;

– Establishment and management of inspection-based PM;

– Definition and acquisition of materials and parts to be used [e.g., lubricants (food grade versus non-food grade)];

– PM activities, requirements, and checklists;

– Evaluation and documentation for addressing deviations;

– Sources of technical data and drawings [e.g., floor plans, Piping and Instrument Drawing/ Diagrams];

– Change control for PM (e.g., the definition of Like-for-Like);

– Removal from and return to service for PM activities;

Calibration
Instrument Specifications include, and are not limited to, the following:

– Definition of required accuracy and precision;

– Expected Process Parameter values, including unit of measure;

– Expected Normal Operating Range (NOR) of the process parameter values;

– Acceptable tolerance;

– Instrument stability requirements; and

– Safety and environmental considerations.

Evaluation Process Supporting Elimination of Defined Shipment Temperature Range
Some GMP sites may be practicing to ship some oral dosage form products from manufacturing facilities to Distribution Centers under controlled (defined temperature range) temperature conditions.

Determining Testing Patterns and Acceptance Criteria for Analytical Method Transfers
When an API or a single strength of a drug product is being transferred, a minimum of one lot may be used for the AMTE. If a single lot is to be used, it is recommended that the testing pattern include multiple analysts, multiple days, and /or multiple instruments to assess the Receiving Laboratory’s (RL) ability to generate consistent, reproducible results. Where multiple lots or batches are used for the transfer, the

Quality Risk Management Application to Establishment of Weighing Device Performance Testing Intervals
This guidance document applies to weighing devices used in all aspects of operations. The phrase “performance verification” is representative of testing conducted using certified, traceable weights representing the upper and lower ends of the established working ranges for a specific weighing device.

Analytical Laboratory Management
All Original Sample Solutions, Standard Solutions, Glassware, and Reagents used in the analysis and in any subsequent investigation should be retained to the extent possible if an analytical laboratory investigation (LI) is required.

Microbiology Laboratory Management
An Inventory of Major Equipment in the Microbiology Laboratory should be maintained and include, at least, the following information:

– Equipment name, manufacturer, and model number;

– Date of installation; and

– Equipment identification (e.g., asset or serial number).

Transfer of Analytical Methods

– Identify the qualified personnel to lead, execute, and complete the transfer activities. If a facilitator or 3rd laboratory is used, then their responsibilities should also be identified;

– Provide method-specific information to the Receiving Laboratory qualified personnel;

– Provide method-specific training and support to Receiving laboratory-qualified personnel, as applicable;

– Generate, review, and approve transfer documents;

Quality Agreements
Quality Agreement – a document between the buyer site and a contractor or supplier of material that defines the roles and responsibilities of the two parties’ quality-related functions.

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Aseptic Area Guidance

Alternatives to Formaldehyde Fogging of Clean Rooms
Alternatives to formaldehyde fogging include using liquid sanitisers or fogging with an alternate chemical sterilant such as chlorine dioxide, vapour-phase hydrogen peroxide, or atomised peroxyacetic acid-hydrogen peroxide. For biological facilities where viral contamination is a concern, it may be a regulatory expectation to decontaminate via fogging with some frequency.

Clean Steam Systems
Quality Monitoring of the feed water should be performed according to established procedures and schedules.

Cleaning and Sterilization of Aseptic Manufacturing Equipment
Washing Bays for Initial Cleaning and Final Rinsing of Equipment should include, and not be limited to, the following design considerations:

– Floors sloped to a drain;

– A minimum two (2) inch (5cm) air break to drains;

– Water contained and drained within the washing bay;

– Ventilated area to minimise condensation on ceilings and walls; and

– Utilities identified (e.g., water, filtered compressed air).

Container Closure Integrity for Sterile Drug Products
The Suitability of the Container Closure System should be confirmed by testing the quality attributes of the drug product over its shelf life.

Controlling the Microbiological Quality of Solid Oral Dosage Forms
A documented risk assessment should consider the facility, equipment, materials, and personnel as related to the potential contribution of microbial contamination to the final SOD (Solid Oral Dosage) product. The level of risk determined from this assessment will assist in formulating the microbiological control program.

Defining Worst Case Conditions for Aseptic Process Simulations
Aseptic process simulation tests (e.g. media fills) “are used extensively and are recognised as an effective way to validate aseptic filling” processes to comply with regulatory GMP expectations. A media fill begins at the point where the final sterilisation of the product takes place (i.e. where aseptic operations are performed) through the completion of filling operations with the sealing of the filled containers.

Evaluation of Repeat Testing and Retesting During Microbiological OOS Investigation
During a laboratory investigation, confusion may arise regarding the difference between these terms and their overall purpose. This document provides a more detailed explanation of these differences and the individual importance of these tools during a microbiological OOS laboratory investigation. In addition, this guidance will also briefly clarify the similarities and differences between these definitions as compared to analytical OOS laboratory investigations.

Gamma Radiation Sterilization
Critical Process Parameters for gamma radiation sterilisation include:

– Exposure time,

– Timer setting (batch mode processing),

– Conveyor speed (continuous mode processing),

– Package size and bulk density, and

– Dose measurement.

These parameters should be monitored or controlled and documented on the sterilisation record.

Lyophilisation
Collapse Temperature – in the lyophilisation of amorphous systems, that temperature below which primary drying must occur to prevent loss of product cake structure (i.e. melt back)

Microbial Attributes Testing of Non-Sterile Solid Oral Dosage Forms and Materials
It is not mandatory to examine the microbial quality of drug product raw materials, non-sterile excipients, APIs, and finished solid oral drug products unless required by the compendia or a regulatory filing. However, a microbial assessment should be performed on all raw materials, non-sterile excipients, APIs, and finished drug products that are not required to be tested by compendia or regulatory filing. This assessment will determine if testing for microbial attributes is warranted.

Microbiological Testing in Cleaning Validation
Microbial control should be considered for cleaning procedures that provide conditions favourable to the growth of microorganisms. If the risk of the growth of microorganisms is high, microbiological sampling of product contact surfaces is one activity that can demonstrate that the cleaning process does not contribute to the increase of the microbial load above previously defined acceptable levels.

Overview of Trending of Environmental Monitoring Data
It is a regulatory expectation 1,2 that producers of aseptically produced drug products understand how the environment affects their products. From a microbiological perspective, this means a review of environmental monitoring (EM) results from each batch supplemented with a periodic review of EM data over extended periods of time.

Packaging System Integrity for Sterile Medical Devices
The Suitability of a Packaging System should be confirmed by testing the quality attributes of the medical device over its shelf life.

Cross Contamination Prevention
Facility Design should include consideration of, and not be limited to, the following items:

– Room and equipment layouts that minimise potential cross-contamination of products (e.g. use of airlocks);

– Use of closed processing equipment;

– Air quality, airflow requirements, and air re-circulation controls;

– Product and material flow;

– Personnel flow and gowning requirements;

– Collection, transportation, and storage of waste;

– Drainage systems; and

– Cleanable continuous, smooth, and non-porous floors, walls, doors, and ceilings with surfaces able to withstand repeated application of cleaning agents.

Prevention and Control of Fungal Contamination in Tablets
Tablets are generally considered to be a self-preserved dosage form that possesses an inhospitable environment to most microorganisms because of the lack of available water. Still, many fungi (mould) populations, if introduced before or during manufacturing, can potentially survive (in a static state) or proliferate on or within the final tablet dosage form if the correct conditions are present.

Sanitant Rotation in a Routine Sanitization Program
The definition of sanitant acceptability, as stated in 40 CFR 156, indicates that sanitisation products for use on non-food contact surfaces achieve at least a 99.9% (3-log) reduction in the number of test microorganisms over the parallel control count within 5 minutes

Sterilisation/Depyrogenation Validation for Equipment and Containers
Preventive Maintenance (PM) Measures should include, and not be limited to, the following: For Steam

– Calibrate instruments and elements (I/Es);

– Check the operation of vacuum pumps;

– Clean chamber, steam traps, and drains;

– Perform leak test of the chamber; Replace and integrity test vent filter;

– Verify the operation of safety devices; and

– Check door seals and gaskets for deterioration.

Unplanned Clean-room Power Outage Time Limit and Recovery
An interruption of power supply to the HVAC systems may produce a “loss of control”, which can be defined as a breach in the integrity of the controlled areas in sterile manufacturing. Appropriate steps are to be taken during and after an interruption of air supply to the aseptic processing area (APA). (These steps should be included in site procedures before the studies recommended in this document are executed.)

Use of Sterilized Goggles Within the Aseptic Processing Area
This guidance provides background information forming the basis for the requirement for sterilised goggles and discusses goggle availability, sterilisation compatibility, and program considerations.

Water Activity in Pharmaceutical Manufacturing
Though the principles of water activity (e.g. salting, drying, mummification) have been used for centuries, their use by the FDA occurred in the 1980s when water activity testing was added to existing strategies for microbiological control in food products. Water activity is significant to the pharmaceutical industry in that it affects the quality of ingredients and finished products through their chemical stability, a reduced need for chemical preservatives, and a potential reduction in the need for microbial limits testing.

Quality Management System Manuals

Evaluation of Contaminant Options for Packing of Solid Dosage Forms
The purpose of this Guideline is to provide a robust logical and guidance document to: Assist in the evaluation of actions required in the design, construction, and operation of Packing Facilities; Assist in the clarification of health/hygiene and Good Manufacturing Practice (GMP) issues; Be used as a tool to assist in the selection of equipment and facilities for packing operations; Encourage the use of the risk assessment model when considering both health and hygiene and GMP.

Retention and Disposal of GMP Documents and Retention Samples
This procedure covers GMP and Medical Device documentation and Reference/Reserve samples for Active Pharmaceutical Ingredients (APIs), Intermediates, Formulated Products, Starting Materials Packaging Materials, and Finished Products. (Note: No reference/reserve samples of Medical Devices are required).

Certificate of Materials Supplied
A certified material is a material provided to the receiving site, by a supplier, that is released by a sister site, or released by a contractor directly into the site’s distribution chain, without repeat laboratory testing by the receiving site or an independent laboratory approved by the receiving site, unless such testing is necessary to meet cGMP requirements, e.g. identity testing and/or local import regulations.

Quality Agreements
A written and binding agreement between a Contract Giver and Contract Acceptor that clearly defines the roles and responsibilities of each party in the provision of a service to ensure that all quality attributes consistently meet the contract giver’s and cGMP requirements.

Procedure for Quality Assurance Management for Contractors
This procedure is applicable to the management of contractors to contract giver Operations that supply APIs, API intermediates and starting materials, bulk formulated products, finished packs, QC testing, distribution, and commercial stability studies.

Regulatory Inspection Guideline
This guideline covers GLP, GCP, and GMP inspections of manufacturing functions, departments, clinical investigation facilities, Pharmacovigilance programs, and R&D or manufacturing sites by Regulatory Authorities including ‘Notified Bodies’ in the case of medical devices and diagnostics. It also includes Information Services (and any associated third-party providers) in support of the GXP-regulated computerized systems.

Quality and Compliance Auditing
This Guideline is applicable to all pharmaceutical manufacturing sites, functions, and departments undertaking work or providing support services, required to meet Good Laboratory Practice (GLP), Good Clinical Practice (GCP), Good Manufacturing Practice (GMP), and/or International Organization for Standardization (ISO) standards.

Auditor Training
This guideline is applicable to all manufacturing Operations and Research and Development sites, for staff performing GMP Quality & Compliance Audits externally of company suppliers and internally of its sites.

Facility Based R&D QA Audit
A controlled document is one that is maintained in such a way as to prevent or track changes that are made to it, is it signed and dated, and retained in the QA files.

Compliance Improvements Plans for GMP Facility
It is the responsibility of the management of each function, department, manufacturing site, or marketing company to regularly monitor the compliance status of their operations. Management should generate a Compliance Improvement Plan (CIP) as a result of their review. Quality Risk Management should be applied to prioritize any improvement areas identified.

Archiving, Disposal,the and Record Management Guideline

Records of the same provenance or origin accumulated by an organization or person in the course of conduct of business affairs, and preserved because of their enduring value.

Internal Quality Assurance Agreements
The QA Agreement supports the arrangements defined within the Supply Agreement and should complement the Supply arrangement by defining the responsibility of each party regarding Quality Control and Quality Assurance.

Audit of a Distribution Site
Critical Observation: “Deficiencies with Company Standards, and/or current regulatory expectations that provide an immediate and significant risk to product quality, patient safety or data integrity, or a combination/repetition of major deficiencies that indicate a critical failure of systems.” Immediate corrective action and reporting to Management is required.

Supplier Auditing for GMP Facility
This Guideline is applicable to all manufacturing Operations and Research and Development sites performing audits of suppliers used by the buyer company. This includes routine audits, “for-cause” audits, and initial supplier selection audits.

Management of Master GMP Document
An approved, version-controlled GMP document is any policy, procedure, guideline, protocol, report, controlled form, or template in paper or electronic form that is required for compliance with the GMP codes of practice and/or company Standards.

Artwork Creation & Control of Printed Packaging Components
The Marketing Company is the organization responsible for marketing products in a country. For the purposes of this Guideline, the definition of a Marketing Company includes any manufacturing and/or packaging sites that may be part of the Marketing Company organization.

Release of API Bulk Formulated Products & Part Finished Packs
The site QA Manager is responsible for ensuring that there are procedures and systems in place that ensure only materials fit for use are released to the appropriate Operations Site or market.

Computerized Systems Risk Management
The systematic and comprehensive identification and understanding of risk factors and their associated risks, together with a decision-making process to implement appropriate controls.

Cross Contamination Risk Evaluation Process for Commercial Compounds
Cross contamination risk evaluation guideline applies to the manufacture of commercial or development products in Operations facilities. It also applies to the manufacture of commercial or NPI (New Product Introduction) products at contractors. It is applicable to all Operations and Research and Development sites involved in these activities.

Certificate of Analysis & Certificate of Manufacture
This Guideline is applicable to all Operations sites issuing CofA and C of M. For materials distributed to other sister sites or customers for commercial use. BSD used for compliance, importation, financial, and regulatory purposes is within the scope of this procedure. For products received from an external source, the Operations Site concerned should require the same standard of documentation.

Annual Product Reviews & Product Quality Reviews
Product quality review should be conducted at least annually, to assess the quality standard of each drug product with the objective of verifying the consistency of existing processes and the appropriateness of current specifications, and highlighting any trends, in order to determine the need for changes in drug product specifications or manufacturing or control procedures.

Warehousing and Distribution of Commercial Products
API: Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

Utility Standards
Potable Water (Non – Compendial Water): Water, that as a minimum, meets national standards for water intended for human consumption that have been documented as at least equivalent to World Health Organization (WHO) guidelines.

Conducting Investigations
It applies to investigations performed as a result of an incident, problem, or deviation identified in the manufacture, testing, control, and distribution of active pharmaceutical ingredients (API) and drug products.

Management and Documentation of Training
There must be written procedures, defining accountability and responsibilities for establishing and maintaining systems for training. These procedures must define the requirements and scope of training. It is recommended that the training procedures define elements such as:

Definition and Documentation of Raw Data
Raw data are defined as any worksheets, records, memoranda, 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.

Risk Management in the Quality and Compliance Area
The International Conference on Harmonization (ICH) guideline “ICH Q9 Quality Risk Management” forms the basis of this document. It is compatible with the Integrated Risk Management Framework and supports quality risk management within the Project Management Framework.

Deviation Management
It is the responsibility of each site to implement a deviation management system. This system should include the following:

– Tracking of investigations and logging system

– Documentation of the deviations

– Investigation including Root Causes

– Analysis

– Definition of and tracking of appropriate and timely corrective and preventative actions.

– Quality Assurance approval of deviation reports prior to making any product release decision

Guideline for Development and Contents of Specifications
The guideline covers Specifications for non-complex bulk drug substances (APIs) and investigational medicinal products for clinical trials and is also intended for specifications for excipients during the development phase. Specifications for primary packaging material and container closure system are covered in another manual.

QA Audits for Suppliers and Vendors
Suppliers or vendors from external sources for non-clinical safety studies for which a claim of GLP compliance will be made. Examples of key external suppliers or vendors are animals, animal bedding, animal diet, equipment calibration, environmental monitoring, and computer software and validation.

Manufacture Packing and Shipping of Materials Ahead of Full QA Clearance
Manufacture Ahead of Clearance: Manufacturing using the following materials Ahead of Clearance:

– Raw materials for the synthesis of Active Pharmaceutical Ingredients (API).

– Excipients and APIs for the formulation of Bulk Pharmaceutical Products.

– Packaging components for the packaging of finished products.

Determination of Storage Periods for API Excipients Intermediates and Raw Materials
Retest dating and the use of retest periods is the standard method of controlling the use of APIs. APIs shall have initial retest periods based on available stability data assigned in accordance with the tightest international product registration requirements.

Guidelines for Generating Manufacturing Documentations
A Master Formula is a compendium of information that describes all aspects of the manufacture, packaging, and control of an Active Pharmaceutical Ingredient (API) or formulated drug product. It may exist as a single document or, more likely, as a series of separate documents maintained by functional groups within a manufacturing site.

Electronic Records and Electronic Signatures
This guideline applies to any computerized system that creates, modifies, maintains, archives, retrieves, or transmits records required by the predicate rules of GLP, GCP, GMP, or submitted records, electronically in whole or in part in place of paper records.

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Process Validation Manuals

The Preparation of Process Validation Master Plan
A Validation Master Plan is a strategic document that identifies the elements to be validated, the approach to be taken for validation of each element, the organizational responsibilities and the documentation to be produced in order to ensure full consideration is given to product quality aspects. It will show how the separate validation activities are organized and inter-linked. Overall it provides the details and relative timescales for the validation work to be performed.

Process Validation of Bulk Medicinal (API and Intermediate)
Validation Protocol: A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results. Note: for process validation, the protocol would identify the number of validation batches.

Process Validation for Formulated Products
This Guideline is applicable to all Operations, functions, and departments undertaking work, or providing support services, required to meet Good Manufacturing Practice (GMP) or, in the absence of a GMP standard, International Organization for Standardization (ISO) standards.

Cleaning and Cleaning Validation of API Plant and Equipment
Microbiological aspects of cleaning are not considered in detail in this guideline. The risk of microbiological contamination and the associated actions to mitigate this risk should be assessed on a case-by-case basis, e.g. generally equipment is not left water wet. Such risk assessments should consider manufacturing and cleaning operations; materials used in production and cleaning; facility design and controls; API susceptibility to microbial growth and the use of the API.

Sterilization Process Validation
Sterilization: A validated process used to render a product free of all forms of viable microorganisms. In a sterilization process, the nature of microbial death is described by an exponential function. Therefore, the presence of microorganisms on any individual item/ container can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero.

Cleaning and Cleaning Validation for Formulated Products
Microbiological aspects of cleaning and determination of effectiveness are not considered in this document. Such activities should be treated on a case-by-case basis with due consideration given to manufacturing operations, area classifications, dosage forms, etc.

Analytical Laboratory Procedure Validation
All analytical procedures, which are used to generate data that could be included in a regulatory submission, must be validated to the degree appropriate for the phase of development before use. Analytical procedures that are used to test a commercial finished product, raw material, or packaging component, must be validated before use.

The validation of facilities and system
This guideline applies to all types of Facilities and Systems. The validation life cycle model is illustrated in Appendix 1. The life cycle phases indicated in the appendix follow the same sequence as those for computerized systems. The relationship between computerized system validation requirements and the requirements of this guideline should be explained within each individual Validation Master Plan (VMP) or Validation Plan (VP) in the context of the validation being planned.

Information Technology Infrastructure Qualification
The following infrastructure elements are covered by this guideline:

– Local and wide area networks (e.g. data transmission cabling, hubs, routers, bridges, and switches, etc.).

– Servers and mainframe computers (and their operating systems and supporting software products).

– Clients (and their operating systems).

– Peripheral equipment (e.g. networked printers and storage devices)

– Electrical power supply and heating, ventilating, and air conditioning equipment for server rooms and data centers.

– Server rooms and data centers.

– Infrastructure monitoring, management, and maintenance systems.

– Middleware or enabling software., e.g. Oracle, SQL, etc.)

Management of Change in Computerized System
Computerized System: A group of hardware components assembled to perform in conjunction with a set of software programs which, collectively, are designed to perform a specific function or group of functions in a defined environment (including peripheral devices, personnel, and documentation, e.g. manuals, SOPs).

Technology transfer of established medicine from one commercial site to other
The Manufacturing site/s should normally carry out all pharmaceutical processing steps and quality control procedures required to manufacture the finished dosage form and pack this into bulk containers for onward shipment to designated ‘Packing’ sites. However, some products may require enclosure in the final primary container to complete the last processing steps, e.g. sterile products. Sites making such products should be within the definition of a ‘manufacturing ‘ site.

Laboratory Management Manuals

Water Quality Standard
Highly Purified Water: Water produced from Potable Water by methods including, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration or deionization. HPW (Highly Purified Water) meets the same quality standards as WFI (Water for Injections) but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as WFI.

Sterility Testing Procedure
SOPs shall be developed to provide clear direction for the execution of the testing procedures, material preparation, data analysis, and the development of the documentation referred to in this guideline.

Endotoxin Testing
The purpose of this Guideline is to provide a general guideline for endotoxin testing. The guideline should aid in assuring that the products manufactured at any of the company sites as well as by a contract manufacturer meet the appropriate regulatory and company requirements and that there is a harmonized, company-wide approach to the concept of endotoxin testing.

Storage and Expiry Dating of Analytical Reagents in Laboratory
It is the responsibility of each laboratory manager to establish, document, and operate procedures to assign expiry dates to reagents, and solutions prepared from reagents, and record these on each container at the time of receipt (reagents) or preparation (solutions).

Preparation and maintenance of Stability Protocols and Stability Master Plans
The protocol shall be based upon the ICH Stability Guidelines for new products, WHO Guidelines for stability testing programs of pharmaceutical products containing well-established drug substances in conventional dosage forms, and other local guidelines that may be relevant to specific studies.

Commercial Stability Studies at Contractors
The Lead Team/Site (or Quality Assurance Agreement Coordination Team / Site if one is assigned) shall develop a QA Agreement with the contractor that identifies the need, if any, for the contractor to conduct stability studies on material made by the contractor, or in the case of contract laboratories, on study batches provided by the sponsor.

Microbiological Testing for Non-Sterile Medicinal Products
The purpose of this guideline is also to outline the requirements for the analysis of non-sterile drug products as per the harmonized pharmacopeia (Ph Eur, General Text 5.1.4; USP, General Information Chapter <1111>; JP, Chapter to be determined) General Text/Chapters on the microbiological quality of non – sterile pharmaceutical preparations. Herbal medicinal products are outside the scope of this guideline.

Reference & Retention Samples
Samples are retained to fulfill several purposes; to provide a sample for analytical testing, in order to help investigate deviations/complaints as needed, and to provide a sample to the Competent Authority if requested.

Laboratory Equipment Qualification
There are four critical components involved in the generation of reliable and consistent analytical data. The diagram below shows these components as layered activities within a quality triangle. Each layer adds to the overall quality of the data.

Manufacture and Microbiological testing of Sterile Drug Products & API
The guideline applies to the manufacture of sterile products within R&D for human use and for stability studies intended to be filed with regulatory submissions. The guideline applies to aseptically processed as well as terminally sterilized products.

Commercial Stability Testing for Formulated Products
This procedure applies to all drug products. The procedure covers:

– New commercial products – the three first (or early) batches manufactured at each manufacturing site at full-scale production

– Annual Maintenance Stability Testing

– Stability testing associated with product or process modifications

– Stability testing associated with process validation and process deviations

Stability studies conducted as described in the procedure will conform to worldwide registration and QA/GMP/ICH/WHO requirements.

Environmental Monitoring
The guideline provides the requirements for non-viable and microbiological environmental monitoring. This Guideline is applicable to all Operations and Research and Development (R&D) sites, functions, and departments undertaking work or providing support services, required to meet Good Manufacturing Practice (GMP) or, in the absence of a GMP standard, International Organization for Standardization (ISO) standards.

Trending of Stability Data
The registered retest period/shelf life of a drug substance/product will have been set taking into account the specification to be registered and the trends seen in stability studies completed or ongoing at the time of new product and/or new primary pack registration. However, these studies will have been conducted on relatively few batches, some made only at the pilot scale.

Out-of-Specification Results Investigation
For certain tests, including content uniformity, weight uniformity, and dissolution, specific retesting procedures should be applied as defined in relevant pharmacopeias. However, it is recommended that any initial OOS result is documented as described in this guideline and an initial laboratory assessment conducted.

Analytical Procedures and Validation
This guideline applies to qualitative or quantitative analytical procedures that are used to test finished drug products, in-process materials, excipients, raw materials, packaging materials, and Active Pharmaceutical Ingredients (API), in support of regulatory registration documents and in cleaning validation.

Manufacturing Management Manuals

Manufacturing Documentation
All documents to be distributed must have a title describing the purpose of the document and documents must contain:

– Product name or material name

– Date of issue

– Edition/version reference

Information on markets for which the documents are applicable must be available.

Maintenance and Calibration of GMP Critical Items in Manufacturing Operations
Calibration: Set of operations that establish, under specified conditions, the relationship between values of quantities, indicated by a measuring system, or values represented by a material measure or a reference materials, and the corresponding values realized by standards.

Retreatment and Blending of API and formulated Product
For formulated products reprocessing is carried out on products of unacceptable quality so that their quality may be rendered acceptable. For APIs and intermediates reprocessing can also be carried out on a product that meets established specifications e.g. in order to combine smaller amounts.

In-Process Testing, Checks, and Sampling
In-process controls should have the ability to identify when corrective actions are needed and control the performance of processing steps that cause variability in the quality characteristics of products including intermediates and APIs.

Management of Returned Goods
Products that once have left the direct supervision of the company, its joint ventures, licensees, or contractors and have been returned should generally not be accepted for redistribution and should normally be destroyed. However, if traceability and control of the product according to the required storage and transportation conditions can be confirmed, products may be re-distributed on approval by the QA function, (see 5.1.6).

Receipt Handling and Storage of Starting & Packaging Materials
Receiving and dispatching bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

Control of Packaging Operation
The packaging operations should comply with official GMP requirements and any other additional company requirements covered in this Guideline or in other documents authorized by the company.

Management of Change in Manufacturing Operations
The purpose of this procedure is to define the principles for management of change within Operations. This document may apply to the Change Management process, Regulatory Affairs, CMC, and to all cGMP activities performed by Operation sites. It applies to all facilities, processes, systems, and procedures used during manufacture, testing, and distribution that may directly or indirectly affect the quality of pharmaceutical products.

Auditing Principles for GMP Audit
Suppliers are audited to monitor compliance/ quality assurance with GMP regulations and company requirements, evaluate a potential new source or vendor, evaluate key vendor/ contractor changes, or investigate a specific problem being experienced by the firm (for cause). Internal audits of a site are conducted by QA. These audits determine the level of quality and compliance of a particular operation. By conducting these audits, management, both site and quality, can be provided with an unbiased status report of the Site’s Operations. Company internal audits should be performed following a site’s audit program. The quality system should be audited at least on an annual basis.

Understanding Worldwide Regulatory Requirements
The purpose of this training unit is to provide information regarding Worldwide Regulatory Agencies and the regulations that they enforce with respect to manufacturing sites and suppliers.

Depending upon where pharmaceutical sites are located throughout the world and where their products are distributed/marketed each site will need to comply with regulations enforceable by different regulatory agencies. These regulatory agencies are determined by where the drug is manufactured, distributed, and marketed. The regulatory agency will evaluate all sites that take part in the manufacture of the drug product. This oversight includes the range of initial manufacturing steps of the raw materials/APIs to the final packaging sites (primary and secondary). Different regulations are applied depending on the step in the manufacturing process.

Personnel & Training System Audit
Within the pharmaceutical industry, it is agreed that people are the most important element in any pharmaceutical operation. The number of people working at a site needs to be sufficient to ensure that the drug product manufactured, processed, packaged, or held is compliant with all necessary GMP regulatory requirements. Personnel must be qualified and have the right attitude, training, and supervision to produce good quality products.

Deviation Management System Audit
Because QA is responsible for determining the disposition of a production material, it needs to be involved in the investigation process. QA should be notified immediately when a deviation is detected. Management and Quality Assurance are responsible for approving conclusions and actions taken or identified as a result of an investigation.

It is also the responsibility of Management and/or Quality Assurance to ensure that appropriate communication with other impacted functions/sites has taken place as well as to provide copies of final (and interim) reports as appropriate. QA is also expected to oversee the investigation and ensure that it is adequate.

The department responsible for the deviation is expected to conduct the investigation. QA should review and approve all deviation investigations associated with all batches of manufactured products prior to releasing product batches.

Validation System Audit
Validation is the action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material activity, or system consistently leads to the expected results. Documented evidence provides a high degree of assurance that a specific system, equipment, or process will consistently produce a product meeting its predetermined specifications and quality attributes. To put it simply, validation is nothing more than proving that a process actually works.

Change Management System Audit
Planned changes may be proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing, or any other change that may affect product quality or reproducibility of the process. Written procedures should be in place to describe the actions to be taken if such a change is proposed. Change control management should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.

Complaint System Audit
Every effort is made to ensure that drug products that reach the market are safe, pure, effective, and of the highest quality. However, a company may receive complaints from a patient, pharmacist, or physician about a drug product not meeting its specifications. The company or site must know how to manage these complaints. The goal of this training module is to describe how to audit a complaint system using the appropriate GMP standards.

Documentation System Audit
Good documentation is essential for providing assurance that drug products are safe, pure, effective, and of the highest quality. It is expected from any pharmaceutical process. Through the use of established documentation systems, the company and its suppliers are able to provide a complete written record or proof of all activities used in producing a quality drug product. This module focuses on written documentation but data may be recorded by electronic data processing systems, photographs or other reliable means. If electronic systems are used the requirements for the documentation in principle are the same.

Calibration, Preventative Maintenance & Housekeeping System Audit
Calibration of critical items, preventive maintenance, and housekeeping, while not appearing to be the most important parts of GMP, are vital to keep a site in compliance and producing quality product.

Computerized Systems Audit
Any GMP facility whether involved in contract testing, manufacturing, processing, packaging, or distribution will rely to a greater or lesser extent on computerized systems. They are fundamental in ensuring that processes and data are reliable and secure. In order to achieve this they should be maintained in a validated state. Validating a computerized system is establishing documented evidence that provides a high degree of assurance that it will consistently function in accordance with its predetermined specifications and quality attributes throughout its lifecycle.

Utility Systems Audit
To produce either a finished pharmaceutical, an API, an excipient, a medical device, or packaging materials the environment within the plant has to be considered. One of the least noticed but important parts of producing a product free of contamination are the plant utility system. The system includes the heating, ventilation, and air conditioning system (HVAC), the water system, the compressed gas system, and the steam system if used in the plant. Each of these systems must be qualified/validated.

Warehouse and Distribution System Audit
The general requirement for premises is that they should be suitable and adequate to ensure proper storage and distribution of products and any special storage requirements should be met. Thus it is very much the task of the auditor to tour the facilities and to review the activities to be able to come to a conclusion if the requirements are met. One requirement for example is that receiving and dispatch bays should protect goods from the weather. The solution to that requirement may differ very much in different parts of the world depending on the climate. Unauthorized entry to the premises must also be prevented.

Environmental Monitoring System Audit
An environmental monitoring program provides information on the non-viable particulate and microbiological quality of the environment being monitored. Such data provides an insight into the effectiveness of the control programs (e.g. cleaning, housekeeping, gowning, air handling) that are in place. Controlled environments must be monitored using the appropriate regulatory guidelines and industry practices. Areas defined as controlled environments must be monitored as appropriate for that environment. Monitoring programs must be based on the processing requirements of the area and the risk assessment of the area.

Microbiology and Sterility Testing Laboratory Audit
The purpose of this training module is to provide information on what to include in a microbiological and sterility testing laboratory audit. Microbiological testing is used to release products, determine if production environments are satisfactory, and determine if the results of in-process testing are satisfactory.

Analytical Quality & Stability Testing Laboratory Audit
When auditing the laboratory, determine if there have been any recent changes in the laboratory. These could range from the introduction of new analysts or supervisors into the laboratory, changing the organization from a structured, hierarchical system to a team environment, or the implementation of new or different types of testing. The laboratory should be organized to ensure that there are adequate numbers of analysts available on all shifts to perform the workload and adequate supervision for normal hours working.

Material Handling System Audit
Material handling starts when components and packaging materials are received onto a pharmaceutical or Active Pharmaceutical Ingredient (API) plant site and ends when the product/material is distributed. Material includes components or starting materials, (e.g., raw materials), API intermediates excipients, and packaging materials used for APIs or finished products.

Active API Manufacturer Audit
An active pharmaceutical ingredient or API is the therapeutic material found in a drug product. It can be derived from chemical or biological sources. Along with excipients, it is the starting or raw material for a drug product. It is also defined as a drug substance in the ICH Q7A guidance – Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. This GMP guide is a truly harmonized guide developed through the ICH process involving both industry and regulators across the world. The guide is implemented in most parts of the world.

Packaging Material Supplier Audit
Package components are defined as Packing components critical (PCC) or Package components–Non–critical (PCNC). In principle, there are differences between the way ‘Non-critical’ and ‘Critical’ package component suppliers are handled from an auditing view. The difference is that suppliers of critical package components must have an on-site supplier audit, whereas non-critical package component suppliers may only require a Supplier Quality Review (postal review).

This training module will explain some manufacturing methods for package components and key GMP principles that should be considered and reviewed during the audit.

Packaging and Labeling Operation Audit
Packaging and labeling operations are designed to ensure that the finished drug product is free from damage, accurately labeled, and contains what is indicated on the package. The main purpose of labeling is to communicate essential information about medical products to healthcare providers and patients. Packaging and labeling operations must be performed in a manner to minimizes the risk of cross-contamination and mix-ups. It is a fact that a large percentage of all product recalls are caused by errors in packaging or labeling.

Aseptic Sterile Area Audit
A number of dosage forms are required to be sterile e.g. to be without viable microorganisms. Examples of dosage forms required to be sterile are eye – drops, injectables, and large-volume parenterals. They are required to be sterile to ensure the safety of patients, which includes aspects such as route of administration and risks for infections. Sterility cannot however be guaranteed through testing; rather, it is assured through the application of a validated production process.

Auditing an Excipient Supplier
While there is no single regulatory document with the term “excipient” in its name and there are no regulatory requirements that excipients be manufactured for GMPs other than for those excipient categories specified in EU legislation, there are voluntary industry standards that give guidance for applying appropriate GMP principles to excipients. These guidances include those documents used by the International Organization for Standardization (ISO), the World Health Organization (WHO), and the International Pharmaceutical Excipient Council (IPEC).

Auditing an Oral Solid Solution Area
An oral dosage form may be either a liquid or a solid. Each form uses different manufacturing processes and equipment. This is important to an auditor because some items that are critical in one operation may not be critical in another.