change control unit 5 notes.pdf
- 1. A) 6.4 Processing of Intermediate, Bulk Product and Packaging Introduction Pharmaceutical manufacturing operation can be divided into threecategore (a) Intermediate (b) Bulk products c) Packaging of bulkproduc
- 2. Manufacturing Operations and Control 287 These categories of product or rather stages of manufacturing operations can be defined as follows. c a n (al Intermediate product: may be defined as all those stage of materials during manufacturing operations, which the materials undergoes from dispensed stage of a batch materials tili it gets converted into the penultimate stage of formulation ready for primary packaging. b) Bulk product : may be defined as the stage of formulation ready for primary packing. c) Packaging of bulk product : is in fact not a stage of materials but a goods. process of converting bulk product into the saleable transportable These are very important stages in the manufacturing operations and detailed guidelines on GMP about handing these stages of product and process are available in the regulatory literature. Let us have a look at these now. REGULATORY TEXTS AND COMMENTS (a) WHO Guidelines Processing operations Intermediate and bulk products Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, product residues, labels, or documents not required for the current operation. (15.15) Comments This refers to what is called "Line Clearance". The normal thinking is that the line clearance is done for only packaging lines but the same concepts of packaging should be applied to processing operation also. Any necessary in-process controls and environmental controls should be carried out and recorded. (15.16) Comments These records shall be carried out by both production and Q.C. personnel. Some people keep their own records of these i.e. production and Q.C. My personal feeling is that it should be in green ink and production in blue. The biggest advantage of a common document is that the recorded evidences are seen by both the production
- 3. and Q.C. personnel and hence any deviation observed bya. these can be a personnel can immediately be discussed and corrective actof attached t process Jons take Since such documents are part of B.P.C.R. these can be B.P.C.R. and hence you get complete history of the batch.dChe Means should be instituted for indicating fait. o equi at one place. ares ot equipment or of services (e.g. water, gas) to equi til the Defective equipment should be withdrawn from use e defect has been rectified. Production equipment sho stored the cleaned according to detailed written procedures and" be only under clean and dry conditions. (15.17) Each piece of equipment shall have 3 SOPs namely SOP for oper. cleaning and maintenance. These can be part of a single Sopn The equipment should be cleaned immediately after use and co Comments Asing by a clean equipment cover after drying the equipment. Before q ked. The labels should be appropriately fixed on the cleaned equipmens Containers for filling should be cleaned before filling. Attentio should be given to avoiding and removing any Contaminante such as glass fragments and metal particles. (15.18) the equipment the cleanliness of the equipment should be che ent. Comments This clause particularly refers to cleaning of ampoules, vials, bottles eye and ear drops etc. Detailed SOPs related to washing machines should be available and MPCR/BPCR should refer to those relevant SOPs. Any significant deviation from the expected yield should be recorded and investigated. (15.19) Comments Every MPCR/BPCR should clearly specify what yield to expect at each critical stage. If you get the expected yield at every critical stage identified in MPCR/BPCR then you may be sure that the process is going on wel. Any significant variation observed should direct you to investigate the cause and take corrective action, and also take preventive actions to avoid re occurrence of such incidences.
- 4. Manufacturing Operations and Control 289 Checks should be carried out to ensure that pipelines an other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. (15.20) Pipes used for conveying distilled or deionized water and, where appropriate, other waterpipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. (15.21) Comments Water for injection and purified water carrying lines if not handled properly are a great source of microbial contamination and this may result in contaminating product being processed. SOPs should be available for sanitization and sterilization of pipe lines. These lines can be sanitized by hot water flushing through them at regular intervals. The entire line can be closed and filtered. Sterilizing pressure can be passed and then the pipe line can be sterilized. Samples on a rotational basis can be taken from all user points for microbial evaluation. Every user point must get sampled and tested at least once in a week (this is a practical recommendation). In case problems are observed, there frequency of sampling and testing can be increased. Appropriate action and alert limits should be clearly specified and followed. Records of sampling, sanitization arnd sterilization of pipes should be maintained. It is advisable to periodically review the results of such microbial analysis and to study the trend and take corrective and preventive actions whenever required. Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at pre-specified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated. (15.22) Comments All measuring devices must always be in a stage of perfect calibration.
- 5. 200 cGMP for Pharmaceuticals m master calibration plan for all measuring devices shouled be in the form of a matrix giving instrument deseription instr e number and wrekly plan for calibration. Generally an yearlysch is made in consultation with the user department. The exact cd by the metrology. valicdation or Q.C. departments. It should a the user department and the calibrating agency. Recalibration should also be fixed and written on the certificate. the week should be finalized preferably in advance to suit botn ate A set of calibration SOPs should be available and recorde calibration carried out (calibration certificate) must be available o es. appropriate departments like, validation, metrology, Q.C., engineeri This certificate can be presented on demand by the authoriti. Particular attention should be given to the primary standards rds. validation and its tracing back to national or international standard Validity of date of the primary validation instrument must be checko f the calibration validity of the instrument, against which th. instrument is being checked, has crossed its expiry date, then th calibration done with such instrument automatically stands invalid Repair and maintenance operations should not present an hazard to the quality of the products. (15.23) any Comments Most of the new pharmaceutical plants are now designed with a service corridor. This concept avoids direct entry of the maintenanco personnel in the processing area and naturally risk of contamination of the processing materials is reduced substantially. It is very much useful for equipment like fluid bed dryers, big powder blenders etc, In other cases, before the maintenance is undertaken, the area must be freed from any processing materials. And after the work is over the equipment must be thoroughly cleaned and taken back into operation. Machine log book should be entered for dates of maintenance, cleaning and operation. The record must be signed and dated by appropriately authorized person. Packaging operations When the programme for packaging operations is being set up, particular attention should be given to minimizing the
- 6. Manulacturing Operations and Control 291 risk of cross-contamination, mix-ups, or substitution. Different products should not be packaged in close proximiuy unless there is physical segregation or the use of electronic surveillance. (15.24) Comments At least 1 to 1.2 meter high spatial separation should be done between two adjacent packaging lines. All materials of previous batches must be removed. Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printinng machines, and other equipment are clean and free from any products, materials, or documents previously used and not required for the current operation. The line clearance should be performed according to an appropriate checklist and recorded. (15.25) Comments There should be an SOP on "Line Clearance". Following points should be covered in this SOP: Removal of all bulk, primary and secondarypackaging materials of the previous batch on the packagirng line. Availability of all bulk and primary and secondary packaging materials of the batch plarnned for packaging. Specifically areas like tablet/capsule hoppers, vibratory disk, channels of strip and blistering machine etc. must be checked thoroughly for complete removal of bulk materials of previous batch. Lower part of conveyer belt is many a time a big culprit for the traces of previous products like a strip or tablets etc. These areas must be very thoroughly cleaned. B.P.C.R. should have a record of such line clearances. The name and batch number of the product being handled should be displayed at each packaging station or line. (15.26)
- 7. 292 cGMP for Pharmaceuticals Comments he The packaging line display board should have following details minimum: 2 Pkg. line No Name of the product Paracetamol Tabs Strength: 500 mg TP1234 B. No 10 x10 strips Pack 01-08-2007 Date This board should be of suitable size, say 30 cm X 20 cm prominently placed on the line. It should be ideally placed facid secondary packaging conveyer belt preferably on the n the packaging cubicle from where the sealed primary packs are Co out for secondary packaging purpose. cm, ing Normally filling and sealing should be followed as quickh possible by labeling. If labeling is delayed, appronria procedures should be applied to ensure that no mix-ups mislabeling can occur. ( 15.27) Comments The major sources of mix-up is partially-complete packagine operations. This generally happens for two reasons, e.g. shortage certain packaging materials and sudden change of packaging schedule to meet certain urgent requirement of other product, which have to be taken on the same line. Sometimes shortage of manpower also i a reason for such partial completion of work. It is a common scenario in many packaging department tosee some bulk tablets, uncartoned strips, unshipped carton, labeled ampoules or vials etc. The main of reason is shortage of packaging| materials. It must be made a rule that no batch will be taken tor packing unless all the packaging materials are available in release state and have been issued to the packaging department. However, if you cannot avoid this situation then you shouldtar at most care to segregate the materials stage-wise, batch-wisea" product-wise to avoid mix-ups. nd
- 8. Manufacturing Operations and Control 293 orrect performance of any printing (for example of code The nbers or expiry dates) done separately or in the course or ging, should be checked and recorded. Attention the packagir thebe paid to printing by hand, which should be rechecked course of shouldbe at regular intervals. (15.28) le hecked Comments (CO of checking first printed sample by Q.C. or1.P.Q.C. is a A S Y s t e m Syctice. The over printed sample, of label, carton or foil must practice. g0od hecked for hecked for the correctness of details like, e . B. No. Expiry and Mfg date Price with proper description if any Mfg lic. (if not already printed). The checked and approved sample should be kept in the B.P.C.R. Special care should be taken when cut labels are used and when overprinting is carried out off-line, and hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mix-ups) On line verification of all labels by automated electronic means can be helpful in preventing mix-ups, but checks should be made to ensure that any electronic code reader, label counters, or similar devices are operating correctly. (15.29) Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. (15.30) Comments Laminated carton and label have a problem of erasing the printed details on them. Appropriate quality of ink should be used for this Purpose, which is of quick drying type and cannot get erased from adninated surface. Alternatively a small window without lamination f the details are embossed the pressure of embossing letters or Created on the laminated cartons or labels, when you overprint on s area it will not get erased or get faded. this Dn number must be so adjusted that you get a correct impression without puncture.
- 9. If labels or other printed materials is bar-coded or . tags then the code or RFID readers can verify that materials is being used. You of course have to see that e are working properly. cGMP for Pharmaceuticals having RT 294 he cort STte that the Teade .Online control of product during packaging should : least checks on: ld includ e aa (a) the general appearance of the packages (b) whether the package are complete materia (c) whether the correct products and packaging are used (d) whether any overprinting is correct the correct functioning of the monitors. (e) Samples taken away form the packaging line shola be returned. (15.31) d no durin Product that has been involved in an unusual event special inspection, investigation, and approval by authori personnel. A detailed record should be kept of this operati (15.32) packaging should be reintroduced into the process only:alte this operatior Comments All unusual incidents which have a potential to adversely affect the quality of the product must be investigated and recorded. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release (15.33) Comments There should be an SOP for reconciliation of bulk and packagine materials and the reconciliation must be done at all critical stag and at the end of the packaging operation. This should become part of the B.P.C.R. Any discrepancies must be identified. investga recorded and corrective actions taken. d batch Upon completion of a packaging operation, any unusdt coded packaging materials should be destroyed a
- 10. Manufacturing Operations and Control e s t followed if estrif ncoded printed materials are returned to stock. uction recorded. A documented procedure should be 295 ( 1 5 . 3 4 ) Comments co d be an SOP toreturn uncoded, printed or other packaging T h e r e s h o u l d be a naterials, erords of such transactions must be made. back to store. This must be done on a materials return n o t e . R e c o r d s Guidelines A A u s t r a l i a ,Critical processes should be validated (5.37) Comments cal processes are Criticeill adversely affect the quality of the product. So for this those processes which if not carried out reason you rocesses arnd maybe he like, mixing, sterile filtration, sterilization, compression of tablet etc. C o r r e tly, will adv vou must identify for each product which are the critical there process must be fully validated such processes Any necessary in-process controls and environmental controls should be carried out and recorded. (5.38) All products and packaging materials to be used should be checked on delivery to the packaging instructions. (5.47) Checks should be made to ensure that any electronic codee readers, label counters or similar devices are working correctly. (5.52) Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. (5.53) Finished products should be held in quarantine until their final release under condition established by the manufacture. (5.58) The evaluation of the finished product and documentation ch is necessary before release of product for sale must be done as described under. Q.C. guide line on release of finished product. (5.59) ter release, finished product should be stored as usable Ck under conditions established by the manufacturer. 5.60)
- 11. 296 cGMP for Pharmaceuticals 1st be cleary No product, even by accident should go to the market witt. goods. Both released by Q.A. Hence, the final finished packs mustt ould remain identified as under-quarantine and released finished goode e Comments oeny them can remain in finished goods warehouse but theysho o to the wo areas of suitable size can be marketed as goods under a n t in segregated area and property labeled. For this purpose ine and goods released. The goods after packing can com dntin quarantine area and rest there till tested and released. Afte th these can be transferred to released goods area. In case unreleased goods (for sterility test) are sent ou parametric release, then care should be taken to see that under not get further distributed without release by Q.C. lab. Theso do can be sent to company's godown and await release informati50d u All the finished goods under quarantine and released ma.... stored as per the storage conditions required. A list of produet be storage conditions must be made by Q.C. and communicated to sto be (c) USFDA Guidelines .There shall be written procedure (SOPs) for production and process control designed to assure that the drug product have the identity, strength, quality and purity they purport or represented to process. Such procedure shall include all requirement in this subpart (F). These written procedures, including any changes, shall be drafted, reviewed , and approved by the appropriate organizational unit and reviewed and approved by quality control unit. (211.100) Comments G.M.P.s first principle under documentation is that if it is not written, it does not exist. For this reason, every activity performed in manufacturing must be identified and described in full details, as how to do it, i.e. you should have SOP for every activity. All these activities must be validated, i.e. proved or established they work as desired and people are trained to carry out these on the shop and implemented. These SOPs must be reviewed periodically whether any improvement can be done for betterment of the proation and, if yes, then these should be changed after sufficient vandalook data is available. Every one concerned should be motivatea o
- 12. Manufacturing Operations and Control 297 for imprOved process but they should not be allowed to effect u change. uniess it IS fully studied, validated, approved and authOrisEu for implementation. When a revised method is implemented previous SOPs related to that must be withdrawn and revised SOP issued Remember that no single process should have two SOPs in place at any point of time. There should be SOP on withdrawal of superseded SOPs in place. All superseded SOPs must come back to the departmern for change control and SOP management (including SOP withdrawal process and records there of. .Written production and product control procedure shall De followed in the execution of various production and process control function and shall be documented at the time or performance. Any deviation from the written procedure shal be recorded and justified. (211.101) Comments Another principle of GMP is: - "Do as you have written (i.e. follow SOPs) and write what you have done (i.e. records)". These records must be completed when the manufacturing activity is being carried out. B.P.C.R. must move along with the product. Incomplete B.P.C.R. is the biggest flaw in the manufacturing system. In 1991 when I was working as a "Plant Manager" in one of the biggest Indian pharmaa company in Dewas, I found one of the plants had about 150 in- complete BPCR. We took a decision to stop the production activity for 3 days (two weekly offs and one working day) and put all the supervisory and managerial staff to complete these incomplete B.P.C.R. and then made it mandatory to see that Q.A. release the product only when they receive completed B.P.C.R. The responsibility of completion of B.P.C.R. was given jointly to the IPQC and production. shop floor people. Procedure shall be utilized to reconcile the quantities of labeling issued, used and returned, and shall require evaluation of discrepancies found between the quantity of drug product finished, and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. Such discrepancies shall be investigated in accordance with 211.192. Labeling reconciliation is waived for cut or roll labeling if a 100% examination for correct labeling is performed in accordance with 211.122 (g) (2) ( 211.125 (c) ).
- 13. 298 cGMP for Pharmaceuticals Comments Reconciliation of bulk and packaging materials must be done a critical stage and not only at the end of the packaging processery gives us a confidence that the process Is going on as desired, A.is at any discrepancy arises then it is easy to investigate and corrif the earliest stage in the process when this discrepancy is f Trect packaging materials. But it is advisable to do the same for alld critical activities. It is a misconception that reconciliation of rne packing materials like label and cartons must be correct till the digit, but that is not true. USFDA allows to set a narrow limits ha F.D.A. insists that this must be done specifically for the nund nted othe printed ditors he and should also be acceptable to all other auditors also, on the historical operational data. It is acCceptable to USFDA audito to manufacturing pharmacist must know this guiding clause to refer the auditors in case of need. Identification and handling of filled drug product container that are set aside and held in unlabeled condition for futura labeling operation to preclude mislabeling of individual containers lot, or portions of lots. Identification to determina name, strength, quantity content lot and control number of each container. (211.130(b)) Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removes from previous operation. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operation have been removed. Result of inspection shall be documented in the batch production records. (211.130(e)) (d) MCC South Africa Guidelines Every effort should be made to ensure that packaging takes place in an orderly manner that will ensure there are no mix ups between one product and another. (6.5.1) Products that are similar in appearance should notDe packaged in close proximity to one another at the same tn (6.5.2) Packaging lines should be well separated and, if possibe physical barriers that will prevent the migration of matera from one line to another should be in place. (6.5.3)
- 14. Manufacturing Operations and Control 299 Special precautions should be taken to prevent the inadvertent transfer of components by personnel moving between packaging lines, e.g. inspection and maintenance stat.(6.3. Process Deviations 6 . 5 Proces deviations can be defined as variation in the production or arny other process from the predefined procedure. Regulatory guidelines discuss this issue and provide guidance as fottów. TEXTS AND COMMENTS EGULATORY (a) TGA Australia Guidelines Any deviation from instruction or procedures should be avoided as far as possible. If a deviation occurs it should be aPproved in writing by a competent person, withthe involvement of the quality control department. When appropriate. (5.15) (b) USFDA Guidelines .Written production of process control procedure shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedure shall be recorded and justified. (211.100(6)) Comments There should be an SOP to control deviations. This is called "SOP on deviation control". This SOP not only deals with process deviations in releasing a materials (raw/packaging) or any process like change in times of mixing. speed of a machine beyond the validated speed. We must remember here that deviations is a one-time change, which is controlled by deviations control system. If the changeis of permanent nature thenit should be controlled by the change control system. .The purpose of controlling and recording deviation is to have a control or rather prevent unauthorized change in the process. .Change control can be initiated by any body through a proper channel as defined in the SOP and followed strictly. Deviation can be taken only after proper approval and authorization by Q.A.
- 15. routinely. Belotu Such change can be taken exceptionally and not routinel the conse 300 cGMP for Pharmaceuticals taking such a change and authorizing it, all the consef ever mee must be evaluated. The finished product must hoWev the same specification as un-deviated product. Such changes are required to be taken during manufas process, when we face a situation of borderline cac.n not Contro es, e materials has specification of moisture content as ne then 1.5% and the testing reveals that it has a moisture e more of 1.7%. If Q.C. production and F and D department feelsi nay b materials can be dried to 1.5% and used, it will not affect he quality of the finished product. In such case deviation me in y taken following the deviation control procedure. Similarlv tablet compression sometimes we find that if I run the mi slightly lower speed than validated range then the product meeh the specification. Then in such cases we may go for deviatinn nlc meets However, a tendency to deviate too often must be discouramn4 by the management. Records of such change must be maintained for further review and corrective and preventive action purpose 6.6 Charge in of Components The concept of "charge in of components" is advocated by U.S.F.D.A. This concept came into existence with a view to assure that the pharmaceutical products have the desired strength and quality of the product. There should be a SOP to provide guide lines on this. REGULATORY TEXTS AND COMMENTs (a) USFDA Guidelines Written production and control procedures shall includethe following which are designed to assure that the drug products produced have the identity, strength, quality and purity the purport or are represented to possess. The batch shall be formulated with the intent to provia not less than 100 percent of the labeled or establisheu amount of active ingredients. (211.101(a)) (a)
- 16. Manufacturing Operations and Control 301 Lomments addition ofthe active ingredients to the calculated ers to ad d also to adjust the assay or potency of the active substance s n o u n t . A n d o 1 0 0p e r c e r indalso i Pont. This means if a tablet is claimed to be containing T h i s r e f e r he active substance and if we have the released ac ctive s r e l e a s e d a r eleaf adding 500 mg the substance we must add 506.07 mg or substance o f 9 8 . 8 % stanat 98.8 % it should be actually adjusted to 100% means ng of the n m f 98.8% assay or potency then eventhough the material instead tive substand steaesubstance. This calculation must be recorded in B.P.C.R. t h e . Components of drug product manufacturing shall be (b) weighed, measured, or subdivided as appropriate. If a component is removed form the original containers to another, the new container shall be identified with the following information. 1. Component name or item code 2. Receving or control numbers 3. Weight or measure in new container 4. Batch for which the component was dispensed, including the product name, strength, and lot number. (211.101b)) Comments This activity relates to dispensing of the active materials. Hence we must add that the weighing details must also give the details about net, tare and gross weight in the containers so that the manufacturing pharmacist can check all these 3 by weighing before addition of the materials for mixing with other ingredients. Since verification by weighing is easier and more accurate, even liquidis mUst be dispensed by weight rather than volume. (c) Weighing, measuring. or subdividing operation for components shall be adequately supervised. Each Container of component dispensed to manufacturinng shall be examined by second person to assure that, 1. The component was released by the quality control unit. . The weight or measure is correct as stated in the batch production record. . The containers are properly identified. (211.101(c)
- 17. 302 cGMP for Pharmaceuticals Comments In checkingthe second person should preferable be a O.C person. He should check for following things during the dtme operation: he dispensi dispensin (i) Environmental conditions like temp. and humidity in dic. room (ii) Calibration status of the weighing balance (iii) Cleanliness of the materials and area (iv) Differential pressure of the R.L.A.F. unit v Proper observance of the dress-code and protective liances (vi) Release of the materials by Q.C. by verifying the A.R. of raw materials, container and dispensing sheet number (vii) Correct quality of right materials (vii) Any calculation and materials to adjust the assay or potenn. (ix) Proper sealing of containers and labels on them. ncy d) Each component shall be added to the batch bv are person and verified by a second person.(211.101.(d) Comments Normally the process operator adds the materials and production pharmacist supervises the addition and records in the B.P.C.R However, the addition of active substance should also be checked by two persons namely one the production pharmacist and other I.P.QC supervisor and both these people must sign in the B.P.C.R. 67 Calculation of Yield To assure that the process at every stage is going on as desired,citica stages in the process must be identified and limits of expected yield a each of these stage must be defined. B.P.C.R. should record these a any deviations must be justified, investigated and recorded. nd REGULATORY TEXTS AND COMMENTs (a) USFDA Guidelines Actual yields and percentage of theoretical yieldse yield shallbe determined at the conclusion of each appropriate Pa 2seof
- 18. Manufacturing Operations and Control 303 product. onanufacturing, Such processing, packaging and holding of the perso drug aroduct. Such calculation shall be performed by and independently verif ail be performed by one person ad independently verified by a second person person son. (211.10 C o m m e n t s appropriate phases in manufacturing process must be defined T h e a p p r o p r i a r he MPCR/BPCR- on each product and formulation e.8 in he 1. Tablets (a) End of lubrication stage, (b) End of compression, (c) End of coating. (d) End of primary packaging. (e) Finished goods packs. On the similar lines appropriate phases can be decided. This exercise gives us the confidence that the process is going on well and without any problem. Such data should be recorded in B.P.C.R. & Time Limitation on Production Time limitation on production is a techno-commercial issue. Technically it refers to the stability of the product, ifa started product remains ata partially finished stage for unreasonably long period. And commercially it refer to blocked inventory and that means blocked money of the Company without getting the financial returns as expected. REGULATORY TEXTS AND COMMENTS (a) USFDA Guidelines When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. (211.111) Comments Ihe product development document should have established data on Stability and quality of the product to say how long a product can Temain without further processing and without affecting the quality he materials at that stage and so also the quality of the finished
- 19. 304 cGMP for Pharmaceuticals product processed with that material. Such data should be provi to both production and Q.C. department for informationed implementation. and M.P.C.R. and B.P.C.R. should have these limits of time sDecit ified andy. so that the manufacturing pharmacist have these intormation hand. this B.P.C.R. should have records of any deviations observed in regard. 6.9 Reprocessing at Reprocessing is an activity which is carried out on a manufactured batch any stage of processing, when it fails to meet the required specificatio ed ion. This activity is carried out to bring the batch to meet the reguira specification after reprocessing. Following are the available guide line on this topic in the ld regulatory literature. REGULATORY TEXTS AND COMMENTS (a) Schedule M of Dand C act and Rules India Guidelines Where reprocessing is necessary, written procedures shall be established and approved by Q.A. department, that shall specify the conditions and limitations of repeating chemical reactions such reprocessing be validated. (24.1) Comments This guideline seems to be for active pharmaceutical ingredients, where certain chemical reactions must be repeated. Primarily in formulation such situation does not arise, hence I do not comment on thisS. If the product batch has to be reprocessed, the procedure shall be authorised and recorded. An investigation shall be carried out into the causes necessitating re-processing ana appropriate corrective measures shall be taken for prevention of recurrence. Re-processed batch shall be subjected to stability evaluation. (24.2)
- 20. Manufacturing Operatlons and Control 305 C o m m e n t s There should be an SOP to spell out the administrative procedure of re reprocessing of a product, The technical procedure of actually carrying department in consultation with quality and production departments. The SOP on administrative prOcedure should have at least following out reprocessing shall be provided by formulation development points. () Who has recommended the reprocessing and when? (ii) Deficiency observed in testing, which lead to the decision of reprocessing. (ii) Who has taken the decision of reprocessing the batch? (iv) Are stability studies needed? If so how long and by what method? (vWho defines the method of reprocessing? (vi) Copy of the method of reprocessing should be appended to the B.P.C.R. (vii) Batch number may be modified to indicate that the batch is reprocessed. (viii) This batch must be taken in the annual product review, to see if any specific issues observed. Recovery of a product residue may be carried out, if permitted, in the master production and control records by incorporating it in subsequent batches of the product. (24.3) Comments Normally following guidelines can be considered for such residue addition (a) 5% to 10% recovery can be added in a fresh batch. (b) The recovery added should not be more than 3 months old, from the date of manufacturing. (c) Recovery mixture (if from more than one batch ) should be analyzed and if found within specification then only it should be added to the fresh batch. (d) In above condition the date of manutacturing may not be changed for the fresh batch. (e) This batch must undergo in routine stability studies. (0 All information related to such recovery addition should become part of the B.P.C.R.
- 21. 306 cGMP for Pharmaceuticals (b) WHO Guidelines (Ref Section 4.6 in Materials Management chapter) (c) USFDA Guidelines wed Written procedure shall be established and follow prescribing a system for reprocessing batches that do n conform to standard or specification and the steps to be taken to issue that the reprocessed batches will contirm with all established standard specifications and characteristics en (211.115 (b)) Reprocessing shall not be performed without the review and approval of the quality control unit. (211.115(b)) (d) MCC South Africa Guidelines Materials may be reworked or recovered by an appropriate and authorised method, provided that the materials is suitable for such reprocessing, that the resultant product meets its specification, that there is no significant changes in the product quality and that the quality control authorization is obtained. Documentation should accurately record the reworking process carried out. The reprocessing of rejected products should be exceptional. (5.7.1) Residues and re-worked or recovered materials which might adversely affect product quality, efficacy or safety should not be used in subsequent batches. (5.7.2) The treatment of product residues and reworked or recovered materials and the means of their inclusion in a subsequent batch should be specifically authorised and documented. (5.7.3) Limits approved by Q.C. should be established for the amount of any such materials which may be added to a subsequent batch. (5.7.4) Batches incorporating residues should not be released unti the batch which the resides originated have been tested and found suitable for use. (5.7.5) Methods of reprocessing should be specifically authorised an fully documented, once any potential risks have De evaluated and found negligible. (5.7.6)
- 22. 307 Manufacturing Operations and Control The need for additional testing including sterility of auy finished product which has been reprocessed (or to whlcn residue have been added) should be considered. (5.7.) Comments MCC South Africa has given detailed treatment to the issue ol reprocesSing of the product and also addition of recoveries to fresh batches. I personally find the guidelines are very much practical, e.g following 3 points are very practical and seems to have been written after considering the actual situation in the manufacturing. Let us see what these are. (i) It accepts that there may be some non-significant changes in the product quality, which may be acceptable. (5.7.1) (ii) There can be a negligible potential risk. (5.7.6) (iii) The stability of such reprocessed product may be considered. One important point however the guideline takes seriously is that the recovery added must be only from released batches and not otherwise. (5.7.5) As usual it talks about complete documentation arnd approval and authorization of the entire process of reprocessing. 6.10 Drug Product Inspection U.S.F.D.A. guideline talks very clearly about inspection of the packaged and label product. This primarily refers to visual examination (not laboratory testing) of the finishing product on packaging line. REGULATORY TEXTAND COMMENTS (a) USFDA Guidelines Drug Product Inspection (a) Packaged and labeled products shall be examined during finishing operations to provide assurance that containers and packaging in the lot have the correct label. (b) A representative sample of units shall be collected at the completion of finishing operations and shall be visually examined for correct labeling. (c) Results of these examinations shall be recorded in the B.P.C.R. (211.134)