Manufacturing & Packaging Controls PDF

Manufacturing & Packaging Controls Introduction Good manufacturing practices, which are currently acceptable should be followed during carrying out all manufacturing operations and their control. Four key words should always be kept in mind during this, they are: (1) Identity,...

Manufacturing & Packaging Controls Introduction Good manufacturing practices, which are currently acceptable should be followed during carrying out all manufacturing operations and their control. Four key words should always be kept in mind during this, they are: (1) Identity, (2) Strength, (3) Safety, (4) Purity. Since these things will provide the efficacy in the final finished pharmaceutical product. Introduction Identity refers to correct identification of product, people, materials, machines and equipment and locations where the manufacturing operations are carried out. Strength refers to concentration of active substance in the desired quantity in each unit of the finished pharmaceutical product. Safety primarily refers to the safety of the person who is going to consume this product. However safety of the people who produce these product should also be considered. Hence, the manufacturing operations should also be safe, while the products are being manufactured. Purity is nothing but freedom from cross contamination and also from mix-ups. Introduction  To achieve these things: The manufacturing operations must be carried out under the direct supervision of the qualified technical staff (Industrial pharmacists, chemists, microbiologists etc.), who are approved as "Expert Technical Staff" by FDA authorities. The operators and workers who actually carry out the various operations should be trained enough to carry out the activities assigned to them. They should have appropriate knowledge, skill and attitude to carry out their responsibilities. Introduction All materials must be appropriately labelled at each stage; indicating their name, status. B. No., quantity etc., protected throughout the process of manufacturing from getting contaminated and also losing their stability. All containers and equipment must be identified and cleaned to the accepted level. Records of their cleaning, operations and maintenance must be maintained. All activities should be carried out as per approved SOPs and records maintained.  Sanitation of Manufacturing Premises The manufacturing areas where all the production and other related activities are carried out have to be maintained in the state of cleanliness and require sanitary conditions. Certain locations should be marked in each processing area for collection of dust, debris, and waste or trash materials. There may be containers of suitable size and shape made from either plastic, stainless steel or any other suitable materials, a recycled plastic bag can be put into these containers and trash can be collected into it. At regular intervals (say twice in a shift) the collected trash or waste material should be collected, by replacing another plastic bag into it, and deposited at the backside of the plant in a room away from processing area, from where it can be taken to central waste material collection site or scrapyard as per the condition of the waste material. Sanitation of Manufacturing Premises For keeping the premises clean and sanitized, one must use validated cleaning and sanitizing procedures. Cleaning involves using appropriate detergents and disinfectants (difference?) SOP, of facility cleaning should clearly define the detergent and its concentration to be used, the frequency of cleaning, the method of cleaning and persons responsible for doing and supervising the job. After cleaning, the areas should be disinfected by suitable method, using a predefined concentration of disinfectant by specially assigned people at regular intervals, and SOPs and records of such disinfection activities must be made. Sanitation of Manufacturing Premises Records of activities carried out should be made, mentioning date and time of cleaning, and person who performed and supervised the job. Mix-Ups and Cross Contamination (a) Definitions: In pharmaceutical manufacturing, mix-ups and cross contamination poses a big danger and hence necessary precaution and measure should be taken to avoid the same. Mix-ups can be defined as presence of undesired materials into desired materials, which can generally be visibly seen e.g. cartons of one product into another. Tablets of one product with another product which have different size, shapes or color etc. Contamination is also presence of some material where it is not desired. However this may not always be visibly seen, e.g. fine dust of one product into another product; fine black particles of dust into processing materials etc. Mix-Ups and Cross Contamination (b) Sources of contamination and mix-ups: Contamination or mix-ups are presence of undesirable things in desirable material. These contaminants can be from various sources e.g. - Materials - People - Machines and operations - Areas etc. Improper handling of material can lead to spillage on ground and cause contamination, broken containers can leak out material and pose a contamination danger. Dusty uncontrolled activities can contaminate processing environment. Mix-Ups and Cross Contamination People working in the processing area are a powerful source of contamination. They cause contamination mainly from two sources, one by their undisciplined activities in the processing area, and second by their infectious nature of skin or other body parts. Hence, all the people working in the processing should be:  trained in the proper discipline of processing area like, keeping their movements restricted, using hand gloves, masks, proper uniform etc.  medically examined regularly and declared fit to work in the processing area. Mix-Ups and Cross Contamination o Anybody having any infectious disease, or open wound should not be allowed to work in the processing area till he is recovered from this and again declared medically fit to work by a qualified doctor. o People in the processing area should be advised to immediately communicate about their illness, which may adversely affect the products, to their immediate supervisors. This is particularly true if the person is working in aseptic area.  Mix-Ups and Cross Contamination Machines, equipment and equipment related activities is another source of contamination. All equipment must be kept clean and covered when not in use and should be checked before use for their cleanliness to avoid contamination from the previous operation. Similarly, the discharges from any equipment or operation should have control e.g. discharge of exhausted dust, smoke, fumes, gases etc. Moreover, sensitive materials are likely to be discharged in an uncontrolled manner e.g. β-lactam, steroids, highly toxic or potent drugs etc.  Mix-Ups and Cross Contamination Such discharges should be monitored by way of dust collection or water/solvent scrubbing methods to avoid free discharge or such things in the environment. SOPs and records should be kept for cleaning and sanitation of equipment. Mix-Ups and Cross Contamination Manufacturing areas should be classified in various categories of expected cleanliness e.g. aseptic filling area, other sterile operation areas, non-sterile processing areas, corridors, change rooms, outside areas of the plants etc. Detailed SOPs should be written giving details of cleaning methods, materials used for cleaning, cleaning equipment etc. The methods of cleaning and sanitation should be validated. Records of cleaning done should be maintained. Mix-Ups and Cross Contamination (c) Controlling of Contamination and Mix-ups: Certain procedures should be used to control contamination and mix-ups e.g. 1) Exhaust system with proper air filtration and dust collection:  This system should be placed where heavy dust is generated.  Collected dust should be disposed off by suitable method.  Ideal method would be to use closed material handling systems and avoid generation of dust in the first place. Mix-Ups and Cross Contamination 2) Separate air handling units:  These units should be provided for each work-station activities so that a closed circuit air system along with proper air filtration will be operating.  This will avoid particulate contamination from one processing area to other. https://theengineeringmindset.com/air-handling-units- explained/ Mix-Ups and Cross Contamination 3) Depending upon the nature of the products being handled different rooms should be maintained at different air pressure (i.e. negative or positive air pressure) (Normally a difference of 1.5 mm of water gauge in the adjacent rooms is recommended).  Generally more clean area should be maintained at high air pressure, so that less clean air will not enter the cleaner area.  Doors of the rooms should open in the high air pressure area, so that they always remain close. This is in addition to provision of door closures. https://yellowbluetech.com/2019/04/10/clearing-home-negative- Mix-Ups and Cross Contamination 4) Production in segregated areas (which may be required for products such as penicillin's, live vaccines, live bacterial preparations and certain other biologicals), or by campaign (separation in time) followed by appropriate cleaning. 5) Wearing protective clothing in areas where products with special risk of cross contamination are processed. 6) Using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross contamination. 7) Trained people: In pharma processing, the people should be trained in their jobs and also in the principles of cGMP. This will help in avoiding cross-contamination and mix-ups. Mix-Ups and Cross Contamination 8) Packaging lines in the central packaging areas should be well segregated. A partition of at least 1.2 to 1.5 meters is recommended in two adjacent packaging lines. This avoids accidental mix-ups of materials from two adjacent lines. 9) Similar looking products should be avoided to be processed or packed in vicinity of each other. 10) A SOP and record should be maintained for packaging "line- clearance", before starting packaging of a new batch or product on the packaging lines. Line clearance should mean absence of all materials of previous batch packed and presence of all the materials required for the next batch planned for packing on the line. Mix-Ups and Cross Contamination Processing of Intermediate and Bulk Products  Starting from the receipt of raw materials till these materials are converted into bulk goods ready for packaging into their primary and then finished packs, certain points are required to be kept in mind so that the identity, strength, safety and purity of the product is maintained.  Following are some of these points: (i) Before starting any processing, the materials received from the stores should be checked for the identity and quantity. This verification can be done against the labels on their containers and by actually weighing or measuring the quantity of materials. (ii) Process area and equipment must be clean and no traces of previous product should be there. Processing of Intermediate and Bulk Products (iii) All primary containers used for filling of finished products should be clean to the acceptable level of cleanliness. Bulk containers used for storage of in-process materials should also be thoroughly cleaned before use. (iv) Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another area connected in a correct manner. Such pipelines and other pipes used for water etc. should also be thoroughly cleaned and sanitized to get desired level of limits of microbial presence. All pathogenic microbes should always be absent. (v) Environmental conditions must meet the processing requirements e.g. temperature, relative humidity, pressure gradient, class of air, lighting etc., such observations should be recorded in BPCR and other relevant registers etc. Processing of Intermediate and Bulk Products (vi) Yield of materials at all critical stages of operations should be checked e.g. granulation, compression, filling operations of capsules, liquid bottles etc. and compared against theoretical yields expected, any abnormal deviations must be investigated and corrective actions taken. (vii) All measuring, weighing, recording and controlling equipment and instruments should be calibrated regularly so that they always remain in a state of calibration. Records of such calibrations should be maintained. (viii) Repairs and maintenance operations should not present any hazard to the quality of the products. Processing of Intermediate and Bulk Products (ix) All IPQC checks should be carried out at pre-determined stages and deviations should be recorded and investigated. (x) Access to production areas should be restricted only to authorized persons. (xi) Normally, non-medicinal products should not be produced in areas and with the equipment destined for the production of medicinal products. Packaging Operations Similar to manufacturing operations, packaging operations should also have to follow certain precautions to get a good quality product at the end. Following are some of the critical points, which should be remembered while carrying out the packaging operations. (i) Avoid risk of cross-contamination and mix-ups. (ii) All packaging equipment and lines must be cleaned before starting a fresh packaging activity. "Line-clearance" SOP should be followed and records maintained. (iii) Each packaging equipment and line should be identified by a fixed board, indicating minimum following information e.g. - Name of product. - Batch numbers. - Pack size. - Date of packing. Packaging Operations (iv) Normally, filling and sealing should be followed as quickly as possible by labeling and final packing. If labelling is delayed, appropriate steps should be taken to prevent mix-ups. (v) Overprinting on labels, cartons, tablets etc. should be carefully planned and activities clearly segregated to avoid mix-ups. If quantitative records of packaging materials are strictly followed then such dangerous situation can be avoided. (vi) Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. (vii) Laminated cartons or labels should have non-laminated window space for overprinting the batch details or suitable fast drying inks should be used. Packaging Operations (viii) Empty packet detections system in tab/cap. should be used. (ix) Online (personal or automated) packaging checks should be carried out at least for the following things: (a) General appearance of the package. (b) Completeness of package e.g. if a carton has to contain bottle, measuring cup, literature etc. then all such components of the pack should be present. (c) Correctness of pack and packaging materials. (d) Correctness of overprinted details. (e) Weight check of carton. Packaging Operations (x) Products which are involved in an unusual event during packaging operations, should be fully investigated, records made and only when the authorized person is fully satisfied about its inclusion, then only such products may be packed. An additional vigilance by QA department on such batch will be advisable. (xi) Any significant or unusual discrepancy observed during reconciliation of the quantity of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for, before release. (xii) Upon completion of a packaging operation, any unused batch coded packaging materials should be destroyed and the destruction recorded. IPQC in Manufacturing Standard operating procedures should be available and followed for in-process quality control (IPQC) activity during manufacturing and packaging activities. Critical steps should be identified in each formulation process and specifications defined for the parameters to be tested at such stage for manufacturing operations; e.g.: (a) Assay, moisture, angle of repose at end of granulation. (b) Bulk density of granulated material. (c) Physical parameters of compression of tablets like: Weight, Thickness, Hardness, Friability, Disintegration Test, Dissolution etc. (d) Fill weight/volumes in amp./vials/liquid orals etc. (e) pH of solution before filling. (f) Bulk volumes of liquids etc. (g) Environmental conditions verification e.g. Temperature, relative humidity, differential pressure etc. is also a part of IPQC. IPQC in Packaging (a) During packaging operations the packaging lines should be continually monitored to ensure that the integrity of the finished products is not in any way compromised. SOP and tabulated check list should be signed at regular intervals by competent and suitably trained people. (b) Automated controls and monitors should be checked regularly during the production run and validated from time to time. IPQC in Packaging (c) Online control of the product during packaging should include at least the following: (i) General appearance of the package and physical defects if any. (ii) Fill weights, volumes, unit quantities etc. (iii) Completeness of package i.e. the package should contain all components of the pack without fail. (iv) Correctness of all materials used. (v) Correctness of overprinted details. (vi) Correct functioning of all on line monitors (vii) Environmental conditions records e.g. temperature, humidity etc. (viii) Collection of samples for testing and retention should be recorded. Tested or inspected samples should not be returned back. Release of Finished Products Releasing of finishing product is the last activity in the manufacturing and packaging operations at the factory. Once the finished product is released then it can move into the commerce freely. Hence, this is very important activity and should be carried out with most care. While doing this following points should be considered. (i) Finished products must be placed in quarantine in such a way that these cannot be removed for use until such time these are released. (ii) Documentation should be reconciled, completed/and sent for a complete documentation audit by quality assurance. (iii) When all required parameters are satisfied, including the document audit, QC may recommend release of the product from its quarantine status. (iv) The finished product should be released for sale by the authorized person from QA department. Process Deviations Process deviations can be defined as variation, in the production or any other process, from the predefined procedure. Such deviations (drifting from the standard procedures) may adversely affect the desired quality of the pharmaceutical product and hence such deviations should be generally avoided. However, if deviation is exceptionally required, then such deviations must be justified and properly authorized and recorded. If a particular type of deviation is occurring frequently then such deviation must be fully investigated and if required this may be permanently changed through a change control procedure. Time Limitations on Production A pharmaceutical manufacturing process should be completed in a specified time period. Normally, starting and finishing of a pharmaceutical process should be noted and it should be as minimum as possible. If a process involves a number of stages then the maximum time lapse (holding time) between two consecutive stages must be defined and if deviations occur, such deviations must be noted, justified and recorded and made known to the concerned authorized persons. The holding of a product at intermediate stage for abnormally long period have certain potential danger e.g. - Chances of mix-ups. - Stability related problems (Moisture pick up or loss). - Misuse of the material etc. Time Limitations on Production To avoid such problems all critical stages in the manufacturing process should be identified for each formulation and holding time at each such stage must be defined based on the stability data and GMP related issues. This should be done for each product since the stability related issues of each product may be different. These data should be available with the manufacturing pharmacist or alternatively such data may be provided in the BPCR for each product. Expiration Dating The responsibility of the pharmaceutical manufacturer is that the drug product should have the stated potency and therapeutic effectiveness till the end of the shelf life of the product. This shelf life should be based on the stability studies data of the product concerned. For this purpose a detailed SOP on carrying out drug stability studies is required. The data so obtained should be used to establish the shelf life of each product; before it goes into the market. The expiration dates shall be related to any storage conditions stated on the labelling as determined by stability studies carried out. Expiration Dating If the drug product is to be reconstituted at the time of dispensing, its labelling shall bear expiration information for both the reconstituted and un-constituted drug products e.g. in case of dry syrup preparations. Some eye drops are also labelled as how long they can be used after opening the bottle pack. This is in addition to the expiry product of unopened containers. The expiry date should be printed on the label and/or carton or any appropriate primary packaging material. Calculation of Yield According to the CFR-211-103: "The actual yield and percentage of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging or holding of the drug product. Such calculations shall be performed by one person and independently verified by a second person". To meet these requirements each critical stage of the manufacturing process should be identified and theoretical yield at the end of that stage should be established. The actual yield at the end of these stages should be calculated, recorded in BPCR and compared. Yield % x 100 Any abnormal deviation should be recorded and investigated to find out reasons. Steps should be taken to avoid them in future. Calculation of Yield For the common formulations such critical stages are as follows: (A) Tablets: Granulation, Compression, Coating, and Packing. (B) Capsules: Mixing, Filling, and Packing. (C) Liquid orals: Bulk preparation and filtration, Filling, and Packing. (D) Ampoules: Bulk preparation and filtration, Washing of ampoule, Filling and sealing of ampoules, Sterilization of filled ampoules, Visual inspection, Packing etc. Production Record Review The main principle of cGMP is that "The quality of a product is built into it and cannot be just tested in it". This process of building the quality into the product is nothing but the process of assuring the quality of the products. Quality control or testing can test only certain testable parameters only in the final product, but it cannot assure the quality of the product. Testing has certain limitations e.g. test for sterility of a batch of injectable can pass and even then, some of the unit may actually fail in the sterility. This only indicates the limitation of testing or quality control system. Hence, the concept of QA has come into existence. Production Record Review QA not only believes in testing, but it also tries to assure that the entire process of manufacturing has been actually followed, the way it should have been followed. This activity is done with the help of following:  Carry out in process quality check and record them.  Collect samples throughout the manufacturing process on different times, so that it represents the entire manufacturing process in terms of quantity and time.  Check all the documents related to the batch of production, along with quality control documents that means the reviewer should verify the entire production record and when satisfied fully then only release the batch for distribution. Production Record Review In this connection the regulatory literature gives certain important guidelines, which are very important. We will have a quick look at those guidelines. i. All drug product production and control records, including those for packaging and labelling shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. ii. Any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation of such batches shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of such investigation shall be made and shall include the conclusion and follow up.