Process development and basic GMP

Transcription

1 Process development and basic GMP Aulton Chapter 45, handouts Specification, stability, inprocess controls and validation Product development Process development Critical Product Qualities issues Critical Process steps Done for every batch Specification Used as documents on what type of analytical controls to do for products and starting materials Normally done for three batches Stability investigation Used to investigate the shelf-life of a product and to prove that the product is stable during storage FDA/EMEA demands In process controls Used to monitor the process of every batch produced Validation A proof of that the process runs as i should and that it produces product of right quality 1

2 What differentiates production in the pharmaceutical industry from traditional production The requirements on documentation of development, production and changes in production The registration files lock the production method No major changes in the process as described in the registration file can be made The time scale for major changes in production is long The regulatory requirement on validation of the process and analytical methods The requirement for 100% traceability The processes can at be audited not, only by the local authorities but also by FDA. To consider when developing a new process: A product should be possible to produce rationally How easy will it be to adjust the process to changes in market volume, both upwards and downwards? Can the process easily be scaled up? Important when selecting process equipment and production facilities What is needed to develop an effective production from a personnel point of view, number of persons needed, working hours and working environment Does the process require special training of the personnel and how is the production affected if people are sick or if someone quits How should the process be document for registration and for QA purpose? 2

3 Process development Understanding the product quality and its link to production (quality by design) What are the mechanisms of degradation, drug release, and absorption? What are the effects of the product components on quality? What sources of variability are critical? How does the process deal with matters of variability? How to ensure that the process continuously produces products of the preset quality Validation In-process controls Problems when a process is scaled up The handling of larger volumes Changes in the time to perform many unit-operations such as drying The homogeneity of products such as after mixing Effects of production times on working hours Effects on product quality when starting and stopping the process Include production early in development Critical steps in a process A critical step is a part of the process that can affect the final quality of the product Give example on what could be a critical step in a production? Test the limits Test only what is reasonable Decide upon limits early in development process but do not to early Be aware the scaling up may affect some limits When the limits have been established No production allowed outside the limits Validate the process within thesethe limits 3

4 Purpose of IPC Definition Checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms its specification. The control of the environment or equipment may also be regarded as a part of inprocess control. (EU-GMP, Glossary) Can be Part of the release information Can be used instead of final product control - PAT Used for Quality control To make adjustments of the process prior to the start Process surveillance Fill volumes Weight on tablets Process adjustments Via the process parameters Mixing energy Temperature of the out- going air when drying Via product parameters Tablet weight Hardness Part of release It is recognised that a comprehensive set of in-process tests and controls may provide greater assurance of finished product meeting specification than finished product testing. (EU-GMP, Annex 17 Parametric Release, 2.1) IPC- results are more representative for the batch than final control Weight control IPC several hundred tablets Final control 20 tablets PAT ( Process analytical technology) in vogue at the moment Tools in PAT Multivariate tools for design, data acquisition and analysis Process analyzers Process control tools Continuous improvement and knowledgemanagement tools Use of PAT Real time release Reducing production cycle times Preventing rejects, scrap, and reprocessing Increasing automation Improving energy and material use Facilitating continuous production 4

5 Limits for IPC-controlls Based on product development and validation Type of limits Alert limits and Action limits Adjust the process Acceptance limits Remove any material that may have been produced outside the limits Stop the process Quarantine the product Important that all limits be precise and not debatable! Should you accept a product that has a ph of 3.5 if the lower ph limit is 4? Validation Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. There are three types of validations connected with production IQ: Installation qualification OQ:Operation qualification PQ:Performance qualification There is also Validation of analytical methods Design validation Computer validation Cleaning validation 5

6 Validation procedure All processes should be validated All validation work should be planned and according to astandard: Eudralex, described in a validation master plan (VMP) The VMP should contain data on at least the following: (a) validation policy (b) organisational structure of validation activities (c) summary of facilities, systems, equipment and processes to be validated (d) documentation format: the format to be used for protocols and reports (e) planning and scheduling (f) change control (g) reference to existing documents. IQ and OQ IQ Ensures that the equipment is installed correctly installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications collection and collation of supplier operating and working instructions and maintenance requirements calibration requirements verification of materials of construction. OQ Ensures that the equipment functions during operation tests that have been developed from knowledge of processes, systems and equipment tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. 6

7 IQ Ensures that the equipment have been installed correctly Often performed by production Often compared to user requirement documents Should generate SOPs for operations, calibration, etc. An ok on that the equipment fullfills user specifications IQ should include, but not be limited to the following: (a) installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications (b) collection and collation of supplier operating and working instructions and maintenance requirements (c) calibration requirements (d) verification of materials of construction. OQ Secure that equipment works during production Give the right fill volumes, tablet weight, speed of mixing when used for production Should generate Rules for using the equipment SOPs for handling and cleaning the equipment Rules for calibration and revalidation of the equipment OQ should include, but not be limited to the following: (a) tests that have been developed from knowledge of processes, systems and equipment (b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as worst case conditions. 7

8 PQ Process Qualifications Validation of the process as a whole Are normally done during normal production but can be performed using placebo OQ and PQ can often be performed simultaneously PQ should include, but not be limited to the following: (a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment (b) tests to include a condition or set of conditions encompassing upper and lower operating limits. PQ: Performance Qualification To ensure that the right product quality is obtained Identify critical steps in the process Identify which is the critical parameters are in these steps and what values they should be within Set up a test program to check that the critical parameters are within specification Test at least three production batches according to this program Mixing Filtration Filling Capping The challenge to do what is needed but not more 8

9 When to validate New process Existing process Changes in: Equipment Production scale Production site (Raw materials) New guidlines from authorities Revalidation should occur in regular intervals Three types of validations Prospective The norm: all batches should be validated and accepted by authorities before routine production Concurrent Under exceptional circumstances it may be acceptable to not complete a validation programme before routine production starts. Retrospective Validation based on old production records for products that have been accepted without proper validation Prospective Prospective validation should include, but not be limited to the following: (a) short description of the process (b) summary of the critical processing steps to be investigated (c) list of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status (d) finished product specifications for release (e) list of analytical methods, as appropriate (f) proposed in-process controls with acceptance criteria (g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate (h) sampling plan (i) methods for recording and evaluating results (j) functions and responsibilities (k) proposed timetable. 9

10 Concurrent Exception from normal procedure can be made for some products and individual validation batches can be released before the validation is compared The reason for concurrent validation has to be authorised by QP In all other aspects similar to prospective validation Reasons for concurrent validation Short shelf-life of product combined with low sales volume (for example orphan drugs) Important drug where it is of patient interest that it reaches market fast (AIDS) Easier to motivate for changes in production than for new drugs Retrospective Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. Are made on ca representative batcher should be investigated including batches that been outside specifications limits 10

11 After validation Revalidation Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. cgmp: current good manufacturing principle The aim is to ensure quality of the final product and protect patients The rules have often evolved through occurrence of crisis Includes a proper design of the product Includes quality control Described in the guidelines Eudralex:EU laws ICH: International Committee of Harmonisation FDA: Food and drug administration (US) Includes requirements on Production facilities How the process should be performed How each batch should be documented How analytical work should be performed How products and raw materials should be stored How personnel should be trained How faulty products should be withdrawn from market 11

12 The right production facility Has to be uniquely identified Has to protect product and personnel sufficiently. There should allways be locker rooms that differentiat between personal clothes and working clothes Different classes on the quality of the environment depending on what products that are produced Consider whether the products are sensitive to humidity and temperature GMP Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. The proper skills for the job The skills need to be appropriate for the task and includes General GMP training Training in aseptic work Training in the SOPs that govern the work This needs to be documented The responsibilities of all personnel involved in the production should be specified in writing. 12

13 Proper equipment for the production Easy to clean Easy to verify that the equipment has been cleaned Non corrodible material Compatibility between material and the product Plastic material Rubber gaskets, etc. GMP Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. Change control systems 13.10A formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or drug product Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials, and computer software. 13

14 What happens if something goes wrong Out of specification Occurs when a test result is not with in the specified values Actions taken upon an OOS Investigate analytical errors Investigate if it is a true out of specification Decide what to do with the produced batch and if other batches may be affected by the error In the case of a verified laboratory error, it is the retest results that count. The original results and explanation should be retained A confirmed OOS result should result in rejection of the batchs For distributed batches the company is require submit within three working days a field alert report (FAR).The product could be withdrawn from the market Logistic: a key for traceability COMPANY REQUIREMENTS Ensure an effective use of production facilities Ensure short production time Reduce the amounts of product in storage Increase delivery safety to customers Ensure that the raw materials are available GMP - REQUIREMENTS Ensure that products in quarantine are not mixed up with products that are released Guarantee that other mix-ups are avoided Guarantee that all products have a unique identity Guarantee tracability 14

15 Terms to know from today's lecture Process Validation. The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes. Change Control: A formal system by which checks how, proposed or actual changes may affect the validated status of the process. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state. Cleaning Validation: Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products. Concurrent Validation: Validation carried out during routine production of products intended for sale. Design qualification (DQ):The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. Installation Qualification (IQ) The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer s recommendations. Operational Qualification (OQ) The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification (PQ) The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification. 15