Good Manufacturing Practice

Agenda



Good Manufacturing Practices
Contamination
General Employee Hygiene
Food Handling Practices

Good Manufacturing Practices
Deal with contamination
• by people
• by food materials
• by packaging materials
• by hazardous materials
• by miscellaneous materials
General Employee Hygiene
Hygiene
All employees working in direct contact with food, food contact surfaces and
food packaging must conform to hygienic practices. This protects against food
contamination by microorganisms or unwanted material.
Prevent contamination
Careless employee practices can cause product contamination.
The best way to avoid contamination is to prevent it.
How do we prevent contamination?
Any behavior that could result in food contamination such as eating,
use of tobacco, chewing gum or other unhygienic practices, is not allowed
in food handling areas
Hygiene and Communicable Diseases
• clothing
• hair
• personal habits
• hand washing
• personal effects and
jewelry
• illness and disease
• injuries
• visitors
• training
Production employees
• Bathe daily
• No perfume, aftershave, fragrant creams
• No jewellery
• No false nails or nail polish
• Fingernails should be trimmed short
• Use metal detectable bandages covered with gloves
• No eating, drinking or chewing gum
Clothing
• Everyone must wear pants and covered sleeves.

• Cooling product should always be kept covered. . Use yellow cloths to clean the floor and objects (e. • Use gray containers for garbage. Equipment. • Personal belongings and street clothing must be stored in locker rooms. including those holding rework. • Production equipment/utensils must be thoroughly cleaned and sanitized with alcohol after use.• Separate shoes (no open toes or high heels) are to be worn in the factory. No moist cloths are to be left in the production area. Garbage containers must be kept covered. Illness • Doctor’s certificate on hiring • Inform your supervisor or HR if you are ill with symptoms that could contaminate ingredients or products • No medication allowed in factory • Ensure that a clean bandage covers any open wounds Hand washing All employees must wash their hands thoroughly: • when they enter food handling areas • before starting work • after handling contaminated materials • after breaks • after using toilet facilities Food Handling Practices Personnel • Do not leave gloves. • Check ingredients for expiration dates to ensure that fresh ingredients are used. are properly labelled and are kept covered. insects. boxes. mice droppings. • Crates.g. containers or buckets must not be placed directly on the floor. • Report any pests or evidence of pests such as flies. • Store brooms and dust pans at stations provided. Product • Keep hand contact with ingredients to a minimum. Premises • Keep unscreened doors and windows closed. Equipment • Return tools and attachments to their proper place after use. Utensils • Scrapers for moulds and tabletops are not to be used on the floor. step stools) that come into contact with the floor. lying around while on break or at shift end. etc. Cloths Use white cloths to wipe hands regularly and dispose of soiled cloths immediately. masks. containers and utensils • Ensure that all containers. • Use white or brown containers to store ingredients and rework.

• Clean all spills promptly. booties over street shoes. sleeve covers. • Use ingredients in the proper rotation (oldest stock first) • Handle ingredients or products carefully to avoid spilling • Do not return products or ingredients to the production line after they have touched the floor or any other surface that is not clean. Visitors to Production Areas • Should always be accompanied.hair coverings. cutting boards. • Aaaaaaaaaa . • Replace brushes that lose bristles. • Do not handle ingredients or products with either cut or infected hands. • Keep your immediate working area swept or dust mopped. • Sanitize equipment. • Scrape the floor around the work area after completing a job. • Leave your work area clean at the end of your shift. cleaning utensils. • Ensure the production area is clear of all tools and hazards before production starts Retail store • Monitor and maintain proper temperatures • Rotate ingredients using FIFO and check for expired items. sit or step on product surfaces. • Brush off bags and boxes before opening them. • Inspect torn bags and boxes and then repair if appropriate. • Check best before dates and the quality of the food before using. • Work areas should be cleaned regularly throughout the shift. lubricants and paper. • Do not engage in horseplay. • Always wash hands after handling money. work surfaces and utensils. Personnel Practices • Do not lean. etc. Remove any foreign objects or dirt. cords.Check product surfaces before starting equipment. gloves. • Return all tools and attachments to their proper place after use. Receiving and Storage • Ensure that all pallets and materials are kept at least 18” away from the walls. • Keep hand contact with ingredients and product to a minimum. machine parts. • Do not leave maintenance supplies in the product zone. Maintenance and Repairs • Ensure area is segregated from production by use of tarps. • Must be appropriately dressed . • Keep everything off the floor and the area clean and floors swept. Wipe or mop up spilled liquids promptly. • Refrigerate cold foods immediately upon receipt. Sanitation • Keep contact surfaces clean and free of contamination from tools. • Store ingredients and products at the appropriate temperature.

– If deviations occur: should be done in accordance with an approved procedure – approved in writing by a designated person • Checks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits. unexpected contaminants • Mix-ups. • At all time during processing – all materials – bulk containers – major items of equipment – rooms – packaging lines • being used should be labeled or identified • Access to production premises should be restricted to authorized personnel. Good practices in production:General • Any deviation from instructions or procedures should be avoid as far as possible. . GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production • Cross –contamination.Production and Process validation GMP • The good practices outlined are to be considered general guides and they may be adapted to meet individual needs. confusion (false labels) Good practices in production • Principle: production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations. with the objective of obtaining products of the requisite quality. • Operation on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mixup or cross-contamination. Good practices in production:General • All handling of materials and products. – receipt – cleaning – quarantine – sampling – storage – labelling – dispensing – processing – packaging – distribution • should be done in accordance with written procedures and recorded.

Good practices in production: Prevention of cross-contamination during production  When dry materials and products are used in production. skin. In-process controls are usually performed within the production area. – accidental cross-contamination arises from uncontrolled release of dust. etc.g. highly sensitizing materials living organisms. – The performance should not have any negative effect on the quality of the product or another product. sprays or organisms from materials and products in process residues on equipment intruding insects operators’ clothing.• • Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products. particles. pressure differentials and air supply and extraction systems  minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air  wearing protective clothing  using cleaning and decontamination procedures of known effectiveness  using a closed system in production  testing for residues  using cleanliness status labels on equipment  Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOP  Production areas periodic environmental monitoring Good practices in production: Processing operations  Before any processing operation work area and equipment . gases. – proper air control e. hormones. and others  Avoided by taking appropriate technical e. special precaution should be taken to prevent the generation and dissemination of dust. cytotoxic substances.g. – carrying out production in dedicated and self-contained areas – conducting campaign production followed by appropriate cleaning in accordance with a validated cleaning procedure – providing appropriately designed airlocks. – most hazardous. supply and extraction of air of suitable quality  Contamination of a starting material or of a product by another material or product must be avoid. vapours.

water.clean and free from any starting materials. labels or documents not required for the current operation  Any necessary in-process controls and environmental controls should be carried out and recorded  Indicate the failures of equipment or services (e. to fermenter should be used where possible. avoid contamination • Media should be sterilized in situ. products. etc. • Inactivation process: measures should be taken to avoid risk of crosscontamination between treated and untreated products. origin.g. alkalis. method of manufacture. • Validation of sterilization. deforming agents. QC • Media and culture shall be added to fermenter and other vessels under carefully controlled conditions. media. acids. • stored under clean and dry conditions in separate area  Time limits for storage of EQ after cleaning and before use  Containers for filling should be cleaned before filling  Any significant deviation from the expected yield recorded and investigated  Checks pipelines and other pieces of EQ used for transportation of products  Pipe used for conveying distilled or deionized water sanitized and stored according to written procedures (action limits for microbiological contamination and measures  EQ and instruments serviced and calibrated at prespecified interval records maintained checked daily or prior to use clearly indicated the date of calibration and servicing. product residues. . In line sterilizing filters for routine addition of gases. recalibration (label attached to instrument)  Repair and maintenance operations not present any hazard to the quality of the products • GMP for biological products :Production • SOP for manufacturing operations: available. production EQ • cleaned without delay. up date • Starting material: source. • A wide equipment used for chromatography • should be dedicated to purification of one product • should be sterilized or sanitized between batches • define the life span of columns and the sterilization method • In-process controls play a specially important role in ensuring the consistent quality of biological products because certain deficiencies may not be revealed by testing the finished product. gas) to equipment defective EQ withdrawn after use.

process. Validation studies  analytical test  equipment  facility systems (air. Certain operations require the continuous monitoring of data during a production process e.monitoring and recording of physical parameters during fermentation. Samples of intermediate and final products shall be retained in sufficient amount and under appropriate storage conditions to allow the repetition or confirmation of a batch control. but has not been validated according to a prospective protocol and concurrent validation is not realistic option • is not generally accepted  Laboratory-and pilot-scale validations • some production processes cannot be carried out in production facility  removal of impurities by individual purification steps in process  . steam. water. Type of validation  Prospective • pre-planned protocol  Concurrent • base on data collected during actual performance of a process already implemented in a manufacturing facility • suit manufacturers of long standing.g.Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production. equipment. process. unwanted protein.  Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control. contaminating bacteria and virus) spike into process . material.activity or system actually leads to the expected result. sterile filling. • • • Validation: Definition  Validation is the documented act of proving that any procedure. have well-controlled manufacturing process  Retrospective • for production for a long time. lyophilization)  Separate validation for  lyophilizer/ lyophilization process cleaning of glassware/ cleaning of facility sterilization process/ sterility test  verify the system under test under the extremes expected during the process to prove that the system remains in control. cleaning.not acceptable to bring unacceptable impurities (endotoxin. manufacturing processes. sterilization.

IQ. lyophilizer. Process validation studies  examine a process under normal operating conditions to prove that the process is in control  re-validation modification to the process problems occur EQ or systems are changed Process validation  To validate the reproducibility and consistency of a process full defined process is carried out using validated EQ at least 3 times. IQ. PQ EQ: autoclave. IQ. purified water.OQ system: air (HVAC). pure steam. incubator. under established procedure process must successfully and consistently meet all acceptance criteria at all steps throughout the procedure at least 3 times consecutively Validated process Worst case: to ensure that process is acceptable in the extreme case Process validation  Example cleaning sanitization fumigation depyrogenation . WFI. central vacuum. OQ. centrifuge. freezer.Facility systems and equipment: Stage of validation     Design qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)  Systems and EQ. continuous flow centrifuge. oven. PQ=validation  Depending on the function and operation of some EQ Depending on the function and operation of some EQ pH meter. compressed air. PQ Process validation  A process is a series of interrelated functions and activities using a variety of specified actions and EQ which is designed to produce a defined result. raw steam. OQ.

) specification at each step  Very important specifications for a process undergoing validation be pre-determined all critical processing parameters for which specifications have been set. other) endotoxin content reduction of 3 logs Typical content requirements for process validations  Sterile filling test filling process perform filling process with nutrient media run at full scale for at least one fill size . capping. operation capacity. sufficiently detailed to permit complete reproducibility (time period. Fumigation. volume. actual operating range processing parameter. temp.sterilization sterile filling fermentation bulk production purification inactivation filling.etc. there must be equipment to measure all of those parameters during the validation study Typical content requirements for process validations  Cleaning. construction. identity. column chromatography. sealing lyophilization  specific process clearly described in Master formula or in SOP all EQ. Sanitization Process collecting liquid and swab samples for testing of residual product residual protein endotoxin tests microbial tests (bioburden) chemical tests (chlorine and phosphoric acid) residual cleaning agents conductivity tests pH As relevant to the cleaning process All analytical tests must be validated before Typical content requirements for process validations  Sterilization sterilization filtration of solutions microbial challenge filter integrity tests performance tests Typical content requirements for process validations  Depyrogenation process (dry heat. code number. pH.

equipment. and process being validated must pass at all steps Validation: Type of Documentation  Validation master plan (VMP)  Validation protocol (VP)  Validation reports (VR)  Standard operating procedures (SOPs) Master validation plan (MVP)  is a document pertaining to the whole facility that describes which EQ. all facility systems must be monitored 3 consecutive lots must be produced and all facility. PQ for EQ and systems. processing. and additions of nutrients etc. contamination rate of 1/1000. purification. large volume and number of vials filled vials incubated.  provide the format required for each particular validation document (IQ. and facility preparations.g. analytical assay validation)  indicate what information is to be contained within each document  indicate why and when revalidations will be performed  who will decide what validations will be performed  order in which each part of the facility is validated  indicate how to deal with any deviations  state the time interval permitted between each validation Validation: VMP  Enables overview of entire validation project  List items to be validated with planning schedule as its heart  like a map . through to final testing of the batch lot. EQ. observed and test for contamination by validated sterility test must be sterile for 3 consecutive runs media fill performed twice a year size of run must be large enough to detect low levels of contamination e. support systems. in-process tests. sampling. OQ. lyophilization) run according to approved Master formula including all raw material. 3000 units are needed to provide 95% confidence  Mock fermentation full scale fermentation of a representative fermentation process  to validate the parts of process involving connections. process validation. filling. product spec. systems. personnel. bulk production.  fermentor prepared and operated in simulated process with uninoculated nutrient media  process follow the full fermentation process  3 consecutive runs at each stage  Production processes(fermentation. methods and processes will be validated and when they will be validated.worst case.

colourants.  Where ranges of batch size are proposed for production –blending of batches or the use of sub-batches– the acceptability should be addressed. coatings. capsule shells. equipment. processes to be validated  Documentation format for protocols and reports  Planning and scheduling  Change control  Training requirements Validation: Protocol  Objectives of the validation and qualification study  Site of the study  Responsible personnel  Description of the equipment  SOPs  Standards  Criteria for the relevant products and processes Validation: Report  Title  objective of the study  Refer to the protocol  Details of material  Equipment  Programmes and cycles use  Details of procedures and test methods Validation: changes that require revalidation  Software changes. Finished pharmaceutical product(s) [FPP(s)] 3.Validation: In summary. if applicable .  Description of accompanying reconstitution diluent(s). controllers  Site changes. imprinting inks) should be given.g. Malaria and Tuberculosis Section 3.. systems. operational changes  Change of source of material  Change in the process  Significant equipment changes  Production area changes  Support system changes Bbbbbbbb Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS. VMP should contain at least  Validation policy  Organizational structure  Summary of facilities.3 Formulation  Composition of all components that are mixtures (e.

g. or pH. environmental conditions (e. in-process as well as final yields).7 Process validation report 3.g.  Numeric ranges for critical steps should be justified (e.g. at which sampling is carried out for in-process control tests. batch numbers. granules blend for compression. LOD of the compression blend.  In certain cases. protocol number. including packaging. be identified by type (e. intermediate tests or final product controls are conducted should be identified..  Associated numeric values can be presented as an expected range. acceptance criteria). experimentally documented temperature and relative humidity for granules) should be stated. including experimental data) performed at the critical steps of the manufacturing process. tablet cores for film-coating) isolated during the process should be provided. where relevant.. should be indicated.7. at least.6 Manufacturing Process Controls of Critical Steps and Intermediates  Critical Steps: Tests and acceptance criteria should be provided (with justification.  Steps in the process should have the appropriate process parameters identified. The critical steps and points at which process controls.5 Manufacturing process  A flow diagram should be presented giving the steps of the process and showing where materials enter the process.  A copy of the master formula and a copy of a manufacturing record for a real batch should be provided. fluid bed drier) and working capacity. batch sizes. to ensure that the process is controlled. details of sterilization processes and/or aseptic procedures used must be described... 3.  Documented evaluation of at least three (3) production batches (approved batch size) should be submitted to provide assurance that the manufacturing process will reliably meet predetermined specifications. that represents the sequence of steps undertaken and the scale of production should also be provided.g..1 New (for the generic manufacturer) FPPs  Tabulated batch analytical and in-process control data  Certificates of analysis . temperature.  Intermediates: Information on the quality and control of intermediates (e. For sterile products. blending parameters.g. or  Summary of the proposed validation protocol for the critical steps or critical assays used in the manufacturing process (e. testing parameters.3.1 New (for the generic manufacturer) FPPs  Data should be submitted in the application for prequalification demonstrating the validity (batch-to-batch reproducibility of FPP quality) of the manufacturing process..g.7 Process Validation and Evaluation 3. high-speed granulator. tablet hardness.  A narrative description of the manufacturing process. such as time.7. 3.  Summary of the process validation and/or evaluation studies conducted (e. results): 3.  Equipment should. parameters. Stages of manufacture.

manufactured over the period of the last 12 months.1 Specifications for the FPP  Justification of the specifications (e. description of the testing performed. specifications.2 Excipients described in BP. should be used when reviewing the results. regardless of whether .8. or USP  For excipients obtained from sources that are at risk of transmitting Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) agents (e.8. exclusion of certain tests. PhEur. a letter of attestation (with supporting documentation) should be provided confirming that the material is not from a BSE/TSE affected country/area. 3. PhInt. PhEur. peanut oil) demonstrate the absence of aflatoxins or biocides. evolution of tests. ruminant origin). should be listed. such as printing inks.. Batch production records  Unusual findings. A copy of the letter may be found in:  Certificate of analysis for one batch of each excipient from the approved supplier should be provided. PhInt.2 Excipients described in BP.g. All but NLT a total of 10-25 consecutive batches. See Notes page 3. viral safety data) regarding adventitious agents for excipients of human or animal origin: 3.  Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations.g. the content of such impurities could be calculated in relation to their reference standards. analytical procedures.g.7.  Validation of analytical procedures: State if in accordance with ICH or not. and acceptance criteria. or USP  All excipients. (All control methods.7 Process Validation and Evaluation 3. modifications or changes found necessary  Conclusions 3. soy bean oil. Trend analysis should be presented.  Summary of the in-house specifications of compendial excipients and supplementary tests not included in the monograph(s):  For oils of plant origin (e.  List of excipients that are of human or animal origin (including country of origin):  Summary of the information (e. sources.. then its acceptance limits should be calculated with reference to the worst case (API with the smallest area under the curve).. If an impurity results from a chemical reaction between two or more APIs.2 Established (for the generic manufacturer) FPPs  Manufacturing as well as in-process and quality control testing data should be evaluated.g.  Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media. and mention any deviations. even those present in small amounts. differences from compendial standard):  Acceptance criteria for degradants in FDC-FPPs should be established with reference to the API they are derived from. which are present in the product. Alternatively. to provide a statistically significant picture..9.

foil pouches) packaging components:  Identification of the material generally by infrared absorption spectrophotometry. The infrared spectrum of the reference material should be provided: other methods of identification may be appropriate.  Identification of the main additives in particular those which are likely to migrate into the contents (such as antioxidants. a commitment should be made in writing to continue the stability studies post approval. adipates and organic tin compounds). plasticisers. batch size and use of batch tested) must be presented. with indication of the position of characteristic absorption bands.10 Container/closure system(s) and other packaging  Description of the container closure systems. initiators.  Identification of dyes by using chromatographic or any other appropriate method.they are applicable to control at release or to the shelf life should be discussed here).  Shelf life acceptance criteria should be derived from consideration of all available stability information.g.  Report and discuss the results of stability testing as described in Annex 2.  It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.. Organize data for all attributes separately and evaluate each attribute in the report. container size or volume:  Materials of construction of each primary packaging component:  Summary of specifications of each primary and functional secondary (e. including unit count or fill size. When available longterm stability data on primary batches do not cover the proposed shelflife period granted at the time of approval. phthalates. for PVC. etc.  Long-term studies should cover the whole shelf life. The postapproval stability protocol should also be provided and should be the same as that for the primary batches.  Batch analysis results (n=?). The batch analysis must include the results obtained for all specifications at release.. Letter of commitment . place of manufacture.. do these confirm consistency and uniformity of the product? Do they indicate that the process is under control? 3.  Results of not less than three (3) batch analyses (including the date of manufacture.  Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality. catalysts. safety and/or efficacy.11 Stability testing  The design of the formal stability studies for the finished product should be based on knowledge of the behavior and properties of the API and the dosage form. and.. unless otherwise scientifically justified. 3.

. Post-approval commitments The reviewer lists the outstanding commitments. based on the review of the data on quality. information C.  Stability data on three primary batches are to be provided.. D. One of the three batches should be of production scale. Change control  Guidance on variations to a prequalified dossier. Observations. ethanol. Typical deficiencies: List of excipients known to be a safety concern for some patients –e.11. metabisulfites. batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. (Particular problem with artemisinin-derivative FPPs. for a period of time sufficient to cover the whole pre-qualified shelf life (NLT 24 months ending …………………. Date of first marketing authorisation/renewal of the authorisation. which the applicant had undertaken in writing before the FPP was listed on the prequalification list. Recommendations for inspection The reviewer list quality issues identified during the dossier assessment that require verification during a product-specific inspection.  3.  Pharmaceutical data are not counter-checked against the quality part of the submission. <name of applicant> undertake to continue long-term stability testing of <name of FPP> (batch numbers …….12. on the immediate packaging. and ……………………) according to the stability protocol of primary batches.1 Outer packaging or. or tartrazine– are not indicated.  Conditions and requirements for 40 minor changes are detailed. 3. Typical deficiencies include: Number(s) in the national register of FPPs. Overall conclusion Reviewer’s conclusion. Storage instructions do not reflect stability conditions. General remark. if applicable B. 3.We. Typical examples: Change of API manufacturer Change of manufacturing site . batch size. ……….3 Selection of Batches  At the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing. The composition.12. parabens. where there is no outer packaging. Points to be communicated to the applicant A.2 Blisters and strips 3.12 Container labeling  3.g. the remaining two batches at least pilot scale. lactose. gluten.13 Product information for health professionals 3.) and to report any out-of-specification results immediately to WHO.)  The structure of SmPC does not follow that recommended by WHO.14 Patient information and package inserts  Summary of Product Characteristics (SmPC) is frequently not approved by the national DRA.

New scientific understanding and new technologies can provide science.  Batch-to-batch consistency of FPP quality should be achieved through validation and annual evaluation of product and process control results.  ICH guidance Q9 (draft) describes the level of risk-mitigation achieved through quality by design and process understanding. focus on testing as opposed to quality by design). Current regulatory developments  A process is well understood when: all critical sources of variability are identified and explained variability is managed by the process product quality attributes can be accurately and reliably predicted  Process understanding inversely proportional to product quality risk.  Attributes of prequalified FPPs should only be changed after approval of variation by WHO. narrative) and well documented.  Release specifications have to be reviewed at the end of stability studies to establish if change of acceptance criteria is justified. batch size. excipients and primary packing materials should be bought only from approved suppliers. flow diagram. Main points again  The manufacturing process should be clearly defined (site.  Main points again The manufacturing process should be clearly defined (site.  Low efficiency is predominantly due to "self-imposed" constraints in the system (e.  The SmPC and Patients’ leaflet should reflect the design. equipment. development and manufacturing information of the submission. batch size. Current regulatory developments  Pharmaceutical manufacturing operations are inefficient and costly.  Empirical methods are probably approaching their theoretical maximum effectiveness. flow diagram.  Real time product release is on the regulatory horizon. excipients and primary packing materials should be bought only from approved suppliers.  Efforts are primarily directed towards reducing variability in process and product quality characteristics and are not for changing the fundamental design of a manufacturing process.g.Change of batch size  Guideline on stability testing for applications for variations to a prequalified FPP (draft).  APIs. composition.  Batch-to-batch consistency of FPP quality should be achieved through validation and annual evaluation of product and process control results.. static manufacturing processes.and engineering-based approaches. narrative) and well documented. .  Manufacturing processes of innovator and generic manufacturers are fundamentally the same. composition.  APIs. equipment.