whopir_ajanta24-26may2007

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WHOPIR Ajanta, Aurangabad, India May 2007 of 8

World Health Organization Public Inspection Report (WHOPIR)

of the FPP manufacturer Part 1: General information Name of manufacturer Ajanta Pharma Ltd

Paithan Unit Physical exact address b-4/5/6, MIDC Industrial Area

Paithan District 431128 Aurangabad Maharashtra State India

Postal address Corporate Office Ajanta House Charkop, khandivli (West) 400067 Mumbai India

Telephone number + 91 24 31 232123 / 232077 Fax number + 91 24 31 232088 Summary of activities of manufacturer

Manufacturing of products in the following dosage form : - tablets, coated or un-coated, - capsules, - powders (sachets).

Scope of inspection Routine and first inspection of the manufacturing tablets in workshop with special emphasis on the production of Artemether/Lumefantrine 20/120 mg tablets

Date of inspection 24-25-26 May 2007 Programme Prequalification Programme: Priority

Essential Medicines. Part 2: Summary Ajanta Pharma Ltd. is a family-owned company with several divisions, dedicated to the manufactured of medicines for dermatology, cardiology and ophthalmology; it has also divisions for cosmetic products. It also manufactures medicines for foreign markets in the following therapeutic areas: antibiotics, anti-ulcerants, NSAIDs, nutraceuticals, anti-retroviral and antimalarial. The company future plan is to enter American and European markets.



The plant in Aurangabad, Paithan Area, was established in 1983. Basically, it consists in three buildings: an administrative building, the manufacturing plant itself and a building for quality control laboratories; all buildings add up to 4713 sq. m constructed. An extension of the manufacturing building was in progress. The pharmaceutical forms manufactured in the plant are oral solid dosage forms, i.e. tablets (coated and un-coated), capsules and powders (sachets). The site was staffed by 152 workmen, amongst which 73 work the production area, 27 in the QC area and 17 in the QA Department. This inspection was the first time the company was inspected by WHO. The objective of the inspection was to verify compliance with WHO Good Manufacturing Practices, in the framework of the Prequalification Programme: Priority Essential Medicines, and regarding the manufacture of an antimalarial medicinal product. The inspection covered all the areas of activity related to the manufacture of the dosage form tablets, such as:

Quality Assurance. Facilities: HVAC and purified water system. Storage areas. Sampling and dispensing areas, Granulation, compression and primary and secondary packaging. Quality control laboratory.

2.1. Quality Assurance The QA system cover all the relevant activities performed in the site. Product release responsibility of the General Manager of Quality Assurance, hierarchically independent from production. He was responsible also for dealing with other QA related activities, such as handling of complaints, change control and out-of-specifications (OOS) results investigations, internal and external audits, and was supported by enough technical staff of the QA Department. In case of absence, a deputy authorized person can perform product release. All these responsibilities are specified in writing. 2.2 Good Manufacturing Practices for Pharmaceutical products The quality system in place was designed to assure that the products manufactured fulfill the quality requirements, to reduce the risk of mix-ups and contamination. Secondary packaging was a fully manual operation; three lines exist for packaging, with one supervisor each. Blistered products are inspected and rejections from primary packaging are re-processed. No records that quantify or document this re-processing are available. Line clearance was recorded in batch manufacturing records. However, line clearance checklist was not detailed enough to ensure that operators look all locations where products could be.



2.3 Sanitation and Hygiene The level of sanitation and hygiene was acceptable; procedures for cleaning and sanitation were established and covered the essential equipment, facilities and rooms. 2.4 Qualification and Validation A system of qualification and validation was generally in place and protocols and reports on qualification and validation were available. Cleaning validation was reviewed during the inspection. The protocol for cleaning validation was comprehensive and results of cleaning validation studies well documented. The qualification of the fluid bed dryer was reviewed. The operational and performance qualifications were performed in 2004. Some issues raised about this qualification: it was not designed to demonstrate satisfactory operation during the operation range (e.g. maximum load, physical parameters of the load for adequate fluidization…) as well as the limits of its operating conditions (including worst case conditions). In some of the qualification and validation protocols diagrams indicating, for example, sampling points were not detailed enough and could not be considered as satisfactory. One major deficiency was found which were addressed in the corrective action plan. 2.5 Complaints The company has a procedure for handling complaints, which generally meets WHO GMP- requirements. However, references should be included to other related procedures where relevant, such as the product recall procedure. When evaluating complaints, the possibility of counterfeit products should be considered. The complaints records were reviewed during the inspection, as well as the documentation regarding a specific complaint of low content in active substance. 2.6 Product Recalls A procedure for product recall was available. A product recall has never been made. No mock recalls have been made to assess the efficacy of recall procedure arrangements. 2.7 Contract Production and Analysis The company used external contractors for specific analysis techniques (atomic absorption spectroscopy, HPLC with electron absorption detector). Contracts covering these services are available, and Quality Assurance was involved in the preparation of these contracts. 2.8 Self Inspection and Quality Audit A system for periodical self inspections was in place. The procedure for self-inspections was reviewed. The procedure categorizes the deviations in critical/major/minor, but the correspondent corrective actions and follow-up are managed in the same way, disregarding the classification. 2.9 Personnel



The company has sufficient number of qualified personnel to carry out all the tasks for which the manufacturer was responsible. Sporadically, the recruitment of temporary workers was necessary, but, according to the company, these temporary workers are assigned to the less GMP-critical areas. Most of the activities are covered by one working shifts per day, although some requires two shifts per day. 2.10 Training There was a procedure in place for the training of staff covering induction training, ongoing GMP training and on-the-job training. Records were available for each employee summarizing the history of training received. However, only very recently the efficacy of the training activities was being evaluated. Care should be taken with the training of temporary workers. The QA manager was responsible for the approval of the training manual, although this task was not included among his responsibilities in writing. 2.11 Personal Hygiene Personal hygiene procedures including the use of the protective clothing were well established in the production and quality control areas. Personnel entering production areas (Grade D) must wear with shoe-covers, overall, head cover and have their hands disinfected. Jewelry and watches are not permitted in the manufacturing area. However, not all staff working in rooms where the product was exposed was wearing gloves. Gloves were not available for operators working in these areas. 2.12 Premises In general, the buildings and facilities of the inspected plant were appropriately designed and were of a good standard with respect to work flows. However, some deficiencies were observed in this matter. Measures to avoid the entrance of insects and other animals were in place. Internal surfaces in rooms were the product was exposed are not always smooth and easy to clean. For example, light cases project off the ceiling, creating recesses difficult to clean. Grids for air inlets, fixed to the ceiling, are considerably separated from filters; this arrangement makes the upper side of grids difficult to clean. The HVAC system was designed appropriately although it provides adequate conditions for the manufacture of oral solids. Temperature and humidity limits were maintained in the manufacturing area. The humidity limit operational range (45 ± 5 % RH) was not realistic, because the HVAC system could only perform de-humidification, but no device for humidity supply was installed. A more realistic operational range could be the setting of an upper limit for humidity (e.g. less than certain percentage).



During the visit, some records of maintenance operations being performed in the HVAC area were reviewed. Some data about the identity of the equipment or about the operations being performed were not recorded in a timely manner. The purified water plant produces water by two passes of reverse osmosis; water was distributed through a continuous loop, kept at room temperature and sanitized once a week by heat (>80ºC, 60 minutes). Water system was inspected; records of maintenance, sanitization and sampling of the water plant are available. The water system has been qualified. The responsibility for water sampling was not clearly defined. Although the staff declared it was responsibility of Quality Control personnel, the operator working in the water plant declared he does the sampling, which agrees with the information in the logbook. Other discrepancies with the water sampling procedure were detected, i.e. no sterile gloves (as described in SOP) were available for sampling. In the water storage tank a vent filter was installed. The use or maintenance of this vent filter was not recorded. According to the company, this filter was permanently heated, although no records or documentation reflect that situation. Regarding the sanitization conditions, a change of the sanitization time was introduced, without a change control procedure. 2.13 Equipment The production and quality control equipment were generally suited for their intended use, and were generally in good condition. Usage and maintenance operations are recorded in equipment logbooks. Procedures for issue, receipt, storage and destruction of tablet punches and dies exist. Technical specifications should be available for the grease used to lubricate and protect punches and dies. Design of HVAC system was suitable for the activities carried out in the plant. Position of air inlets and returns in the rooms was adequate; however, care should be taken not to block air returns with containers or bins during production. 2.14 Materials The company had developed principles for qualifying suppliers, although some issues were found on this topic. The current version of approved suppliers list needs to be updated, as it does not identify adequately whether the supplier was the original manufacturer or a trader or mediator. A formal assessment and approval of the vendor by QA department of the site was not always performed, as it should be done according to vendor's approval SOP, and some vendors are approved by external (corporate) units. The sampling and testing plan was not modified according to the status of the vendor. Two major observations were made which were addressed in the corrective action plan.



2.15 Documentation Documentation and records exist for al the relevant activities. Almost all standard operating procedures have been recently reviewed. The system for issuance and control of copies of documents was not efficient. Retrieval of copies of obsolete versions was not documented. Several batch manufacturing records were reviewed in detail, including the batches used for validation and the batch used for the bioequivalence study. Some detailed instructions about the operating parameters of certain equipments were missing. For example, milling speed and direction of mill arms should be stated in the instructions given to the operator. A space should be provided in the batch manufacturing record to register the addition of all substances added. 2.16 Good Practices in Production Production operations conducted on campaign based processes were well organized and arranged in a manner that should prevent contamination and cross contamination in the multipurpose plant. However, minor observations were made. In-process sampling was not always documented in manufacturing documentation. For example, no instructions about sampling methods or frequency for sampling are given to perform the sampling for loss-on-drying tests during the drying of the granulate. Unexpected events during production (e.g. power cut), which could have an impact on the process and control of the environment, are not registered in batch record. Some devices (filter bags for fluid bed dryer) are dedicated to the manufacture of one product; however, the identity of the bag (number)was not recorded in batch record. Out of specification (OOS) results are handled, investigated and recorded following a written procedure. This procedure gives the possibility of outlier's rejection, but the cases in which this tool was applied do not follow a valid rationale. Once an OOS result was confirmed, this does not necessarily lead to the rejection of the batch. The confirmed OOS result was submitted to further evaluation prior to batch rejection, but the criteria for such evaluation are not defined anywhere. In the reviews of some manufacturing records, the temperature values of the sealing roller heater were consistently out of the acceptable limits of temperatures for this operation, although leak tests results for blisters were satisfactory. No OOS investigation was issued and this event was not identified as an OOS, incident or a deviation. One major deficiency was found which were addressed in the corrective action plan. 2.17 Good practices in Quality Control The quality control laboratories were well equipped and consisted of chemical and microbiological laboratories with separate rooms. The procedures related to the handling



of reference materials, samples (traceability and identification), specifications and methods of analysis were reviewed and found to be acceptable. The chemistry QC laboratory was provided with equipments suitable for the intended use, correctly maintained and calibrated. Reference standards from official sources are stored in a temperature and humidity controlled environment. However, in-house qualified standards, yet prepared in single use vials, are kept in a non controlled environment (for temperature and humidity). The laboratory has no official reference standards for all the active substances they handle; some of them (arthemeter), which have been recently made available from official bodies, should be ordered. Microbial quality of purified water was monitored following a sampling program. Some findings were related to the sampling and testing of water for microbiological testing. The SOP for preparation and approval of media used in the microbiology laboratory does not include enough instructions to perform the growth promotion test satisfactorily. For example, the instructions do not include details about the volume (cfu) of microorganisms to be inoculated.



Part 3: Conclusion Based on the areas inspected, the people met and the documents reviewed, considering the findings of the inspection and the corrective actions and explanations given the manufacturer Ajanta Pharma Ltd, Paithan Unit, Aurangabad, India ; was considered to be operating at an acceptable level of compliance with WHO GMP. In case a product manufactured on the Paithan Unit is prequalified, a re-inspection within one year is recommended to check the proper implementation of the corrective actions.

whopir_ajanta24-26may2007

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