gmp trends-1

GMP TRENDSEdited Excerpts from actual 483 observation reports

by FDA investigators

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER

FORMULATION DEVELOPMENTFORMULATION DEVELOPMENT

MANUFACTURING CONTROLSMANUFACTURING CONTROLS

QUALITY ASSURANCEQUALITY ASSURANCE

QUALITY CONTROLQUALITY CONTROL

MICROBIOLOGYMICROBIOLOGY

ENGINEERING RELATEDENGINEERING RELATED


FDA CALLS FOR MORE ACTIVE LABORATORY MANAGEMENT

Laboratory managers should not over - delegate primary lab functions to underlings or maintain a lax quality control environment. FDA inspectors are focussing attention on labs having good laboratory practice (GLP) violations that could have been avoided if the manager had played a more active role in the lab’s day - to - day operations. For example, inspectors increasingly are encountering managers who are unaware of testing being done at their labs or who cannot locate samples of the dosage form under analysis, one FDAer told WDL. Comprehensive management of laboratory operations is a “major component” of good lab practices, that source added.

Senior management bears ultimate responsibility for authorization of resources, the establishment of time frames and the overall correction of objectionable conditions, the FDAer noted, and so should be kept informed. Finally, because many labs are using new software programs for data management and for the generation of stability reports, inspectors warn that such software must be independently verified.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER AVERAGING VALUES IS STILL INSPECTION CONCERN

FDA inspectors continue to crack down on drug makers' practice of averaging quality control test results to nudge an otherwise out - of - specification batch into acceptable limits.In the face of increasing evidence that FDA and some firms are approaching GMP compliance from two distinct mathematical schools of thought, inspectors warn against, for example, grouping together validation and quality control test data on multiple batches to achieve pre - established acceptance criteria limits.

For instance, 30 vials of injectable that fail USP weight variation standards averaged in with 60 passing vials cannot support batch release. Also, failing results must be incalidated according to a firm's own release limits, not prevailing USP limits. The cumulative average results of all retested samples must meet a firm's internal standards.

A batch that deviated from established formulation due to equipment malfunction or calculation error may catch inspectors' eyes if no validation data accompany release of that lot. For example a batch exceeding limits for non - active ingredients by 2% may not be released without stability monitoring. Meanwhile, filling operations continue to be an inspection focal point. Some critical fill - related safeguards include :

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER Filter validation for aseptically - filled products. Filling equipment validation must demonstrate that alarms respond as required

when challenged for high and low volume fills. Routine and non - routine equipment maintenance must be documented.

In addition, investigation of out -of - specification results should include identification of any organisms recovered as well as a thorough evaluation of end product quality. Firms should also be prepared to present documentation detailing preventative actions taken to prevent recurrence of the particular problem.

Finally, impurities evaluations should include : determination of the source of impurities ; a validated analytical method to evaluate impurity level ; a determination of the solubility of the impurities ; and evaluation of impurity levels in finished lots on the market. These violations were noted in a Jan. 22 warning letter (*) to Bristol - Myers Squibb at the company's facility located in New Brunswick, N.J.

A Squibb representative told WDL that all matters raised in the warning letter were "addressed and resolved quickly". She said that the particular problems in question focussed on "paperwork" and that product quality was never in question.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER LAB TESTS MUST BE FREQUENT AND COMPLETE, SAYS FDA

Drug labs are getting low marks from inspectors lately for errors ranging from failure to follow through on consumer complaints to failure to conduct certain tests often enough. A thorough investigatory follow - up is in order when customers complain about a product. The single exception to this general maxim is when a complaint centers on an isolated incident, for instance, a problem involving the presence of particulates. In all other cases, the following procedures should not be overlooked :

1. Evaluation of retention samples.2. Review of other batches of the same drug products.3. Review of other drugs that may have been associated with the failure.4. Review of production and control records, such as environmental monitoring.

Though the agency stresses the need for written procedures, existence of such for production tests like stability testing does not guarantee that a facility will pass muster with inspectors. For example, firms can et a citation tests are not performed with sufficient frequency, even if a company follows its written procedures. It is not enough to test for stability only at release and again six months after a product's expiration date, FDAers said. Inspectors want to see stability tests done at release, at a drug's expiration date and annually thereafter.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERFirms also are expected to continually re - evaluate their procedures. For instance, at least annually, quality control should evaluate production, control and distribution records to assess the need for changes to product specifications or control procedures.

That review should be described in a firm's standard operating procedures and the results of each analysis should be documented. FDAers stressed.

Connaught was cited for such GMP deviations, among others, in a Nov. 20 warning letter regarding its Swift water, Penn., facility. Commenting on FDA's requirement for specific action limits for visual inspection of filled containers, a Connaught spokesman told WDL such limits are "based on experience".

CONFLICTING LAB RESULTS RAISE FDA CONCERNS

Drug makers using multiple contract labs should be careful to avoid an inspection pitfall known as "selective reporting". A common scenario is this " Two labs test the pH on samples from the same drug lot, but arrive at two different results, one within specifications, the other out of specification. Quality Control staff may be tempted to keep the "good news" and toss out the bad, but an FDA compliance officer cautioned against doing so.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERSince the odds are equal that either lab's results are correct, it must not be assumed that the in - spec results are the accurate ones, that source warned. Instead, firms must conduct a thorough investigation of both sets of results to pinpoint the reason for the discrepancy. Failure to do so and to document those efforts could spur FDA inspectors to suspect a firm of selectively reporting only favorable results.

Quality control must confirm three threshold points : that the solution tested in both labs was identical ; that both sued the correct method ; and that neither made any technical errors. Certain variables should be reviewed to determine which result should be considered reliable. These include the following :

1. Whether the pH meter was calibrated in accordance with SOPs ?

2. Whether the probe was in good working order ?

3. Whether the calibration solutions were current and appropriate ?

4. Whether the solutions bracketed the specification range ?

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERAfter compiling that information for both labs, quality control should compare the two sets of results side - by - side. Key analysts also should be in interviewed to eliminate any contamination or mishandling of samples. If either seems probable, the result should be invalidated, with the above data as justification. In such case, the source told WDL resampling "would be indicated" and the retest results substituted for the originals.

POST - FAILURE PROCEDURES ARE OF PRIME IMPORTANCE

When a drug makers product lot fails to meet specifications, an immediate and thorough investigation must follow to avoid a warning letter. The foremost consideration is to assure that the lot does not slip past quality control and get released for sale. FDA stresses that batch records must be thoroughly reviewed as part of such an investigation to assure that analytical data support all lots waiting for release.

Release approval must be based on supporting data, not log book review. If a failed lot gets released, failure investigation is key. If a lot fails in uniformity, the cause for any unusual "peaks" in active ingredients must be identified and toxicity determined. Any "strange substances" sources must be found. Searle, of San Juan, Puerto Rico was warned by FDA regarding such problems but could not be reached for comment.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER FDA ENCOURAGES LARGE TEST SAMPLES FOR STERILE DRUG FIRMS

FDA rules do not require that sterile drug makers keep on hand twice the amount of reserve samples required to perform sterility and pyrogen testing. However, they do have to maintain a "sufficient quantity" of samples to perform one such test upon demand. And for many firms, that likely will mean maintaining twice the supplies necessary for other tests, said a compliance officer with FDA's Marketing and Product Quality Division.

The "double sample size exemption" in regulations covering sterile drug sample sizes has for some time caused consternation among drug makers and FDA inspectors alike. The exemption says companies do not have to keep twice the amount of reserve samples to perform sterility and pyrogen tests. But the FDAer said firms should not take the latitude offered by that rule too far.

Sample size for sterile drugs is limited to an amount that can accommodate a single sterility and pyrogen test, for several reasons. First, once a container / closure for a sterile drug is validated, product sterility can be expected to remain stable over time. Second, maintaining twice the sample size needed to run sterility tests in addition to samples for other tests, often is not justified by benefits of keeping the extra units.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERMoreover, sterility testing, by its very nature, does not yield iron - clad results, the FDAer told WDL. For example, such tests are not likely to detect low levels of contaminated units within a given lot. Therefore, when sterility failure is suspected for a distributed lot, reserve sample testing is not as useful in confirming the problem as is a thorough investigation of that lot's production and control records. A related inspection area that is increasingly dogging firms both here and overseas is aseptic processing, including anti - contamination measures for "critical surfaces".

The source stressed that it is every bit as important for firms to validate sterilization of all processes or surfaces that contact sterile drugs or container / closures, as it must validate processes for the drug itself. Microbiological monitoring of surfaces should yield zero colony forming units.

NON - STERILE DRUGS NEED ANTI - MICROBIAL PROCESSES

Drug makers must keep all drugs, not only those purporting to be sterile, free of microbes. The term "non - sterile drug" is merely a term of art when it comes to preventing intrusion by what the agency calls "objectionable micro organisms", an FDAer stressed.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERAdherence to written procedures designed to eradicate microbial contamination of a drug is not peculiar to sterile drugs. But less clear to many drug makers is exactly which microorganisms the agency considers "objectionable". The term's primary meaning, the FDAer explained, is decidedly simple " organisms that can reduce drug safety.

FDA employs a host of criteria to assess a microbe's safety risk, including number and species of the organism, plus the drug's dosage form, intended use, route of administration and target patient population. But the adjective "objectionable" has other, less obvious facets, as well, such as a microorganism's ability to :

Reduce drug stability. React with, or damage integrity of, container / closure systems.

Interfere with analytical methods or active ingredient bio-availability.

The above factors will be most clear for new drugs, for which they likely will have been addressed within the review process and reduced to end - product specifications. The favored method for keeping dangerous microbes in check is setting production time limits, the FDAer told WDL. He emphasized that drug companies should set such limits for "completion of each phase of production" for all products made.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTEROne particular contamination "hot spot",according to the source, is where a bulk topical or liquid drug must be held for several months pending fill. In such cases, firms should set a "holding time limit" to discourage microbial build - up.

CONTAMINATION CHECK SHOULD COVER ALL AREAS

Investigation into contamination of a drug is not unlike the work of a very astute detective, as no stone, however, remote a contaminant source, should be left unturned, according to FDA. When devising a master investigation plan, analysts should assure that their lists include seven broad areas : water, raw materials, equipment, operators, facilities, processing and laboratories. All are equally important, FDAers said.

Within those major categories, there are various bases to cover, depending on where the contaminant is discovered, said an FDA compliance specialist. For instance, in the case of contaminated raw materials, drug firm investigators should focus on foreign matter that might have come from the supplier, such as pencils or pieces of metal.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERInvestigation of raw material storage areas should include a check of the outsides of storage containers, bags and skids. Finally, a raw material investigation must cover sampling areas and sampling scoops, as well as processing areas where weighing, screening and transfer pneumatic systems are found.

Lab equipment often serves as a micro - organism inroad, a phenomenon the FDA source blamed on inadequate cleaning of equipment parts, including components such as lids, domes, valves, seals and dead pockets.

In addition, lab managers should routinely check equipment parts and material that are particularly vulnerable to deterioration. These components typically include seals, gaskets, plastic, Teflon and glass.

Another trouble spot is equipment involved in product transfer, such as hoses, pumps and brushes. The source cautioned firms not to overlook the inadvertent addition of a substance, or cleaning agents as possible sources.

A general facilities review should emphasize trafficked areas of isolation and segregation areas. Lab checks should focus on glassware. Finally, lab operators must be furnished with hair covers, boots, gloves and masks.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER REVIEWED BATCHES MUST SHOW PROCESS “HISTORY”

The number of batches set aside for annual review must tell the full story in terms of any discrepancies, recalls or other problems associated with a given drug. FDA rules call for annual batch review to assess the need for specification or process change.

But the question of how many batches are enough to satisfy the “representative number of batches” part of the rule has caused confusion among drug companies and agency inspectors alike. Firms have a better chance of meeting regulatory expectations if they strive to review batch groups large enough to “exhibit the varying manufacturing experiences” of a given drug, an FDAer said. For instance, batches earmarked for review should represent any and all of the following events that occurred in production : a. Approval, rejection or recallb. Unexplained discrepancies.c. Field alert reportsd. Other outcomes that may indicate needed changes.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERHowever, where multiple problems occurred in any of the above categories, the number of batches selected for review should “fully represent” each type of problem. In addition, FDA’s rule is at least one batch per product, so grouping products based on similar processes is prohibited. Differing processes and / or specifications may result in varying manufacturing outcomes, the FDAer explained.

PROCESSING PARAMETERS CRITICAL TO LOT RELEASE

Pending release of a drug lot for distribution, an attendant validated manufacturing process is as critical as release testing. The release of a product lot without the required process validation data is almost certain to attract inspectors' attention. For parenterals in particular, concurrent process validation studies must encompass all "critical processing parameters", including bulk holding times. For example, data are considered incomplete without established holding times for non - sterile bulks before filtration. Bioburden as well as endotoxin tests also must be done on non - sterile bulks. Inspectors say that such tests must occur during concurrent validation.

FDAers increasingly have stressed calibration of lab equipment.For example, spectrophotometer calibration must include an evaluation of accuracy in the ultraviolet range. Other examples of incomplete calibration include autoinjector calibration sans linearity and accuracy assessments and lack of records that show specific temperatures during polarimeter calibration.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERSuch process validation lapses were noted in a Jan. 27 warning letter sent to Wyeth - Ayerst. In the warning, FDA alleged that holding times for non - sterile bulks prior to sterile filtration were lacking for :

Amikacin Ephedrine NaloxoneAminocaproic Furosemide NeostigmineAtropine Gentamicin PhenobarbitalChlorppromazine Hep-Lock PhenylephrineCyanocobalamin Heparin PhenytoinDiazepam Hydromorphone ProcainamideDigoxin Isoproterenol ProchlorperazineDiphenhydramine Lidocaine / epinephrine ReglanDopamine Lidocaine Robaxin - VDopram Meperidine SMX - TMPDopram - V Metronidazole Sodium chlorideDuramorph Morphine PCA Thiamine

Water for injection

The letter also claimed that process validation data were incomplete for diazepam injection and atracurium besylate. FDA also charged that Wyeth - Ayerst had released lots of bacteriostatic NaCl injection since 1994 without process validation data.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER DRUG COMPANIES MUST DOCUMENT VALIDATION PROPERLY

Documentation to prove validation of manufacturing procedures is critical to GMP compliance, particularly for drug makers performing retrospective validation. Firms that do not provide documentation may face a warning letter.

For example, at an inspection in Shirley, N.Y, FDAers said that company did not document validation of seven unnamed drugs. That failure, along with lack of written procedures for the retrospective approach used to validate older drug, were among charges the agency made to the company.

Regarding the documentation of validation, an FDAer told WDL Luitpold "may feel" that it did, indeed, have all proper paperwork in place, and that the matter is "not at all black or white". It can be difficult, the FDAer said, to distinguish whether a firm has performed validation and failed to document it, or simply never performed validation.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERThe retrospective validation issue is less vague. All companies that perform retrospectives must have written procedures in place, which are followed scrupulously, the FDAer said. Luitpold, he said, clearly did not have such procedures in place when the agency inspector examined the company's facility.

FOLLOW - UP KEY TO BATCH PROCESSING, VALIDATION

Consistent follow - up in batch failure investigation can make the difference between compliance with good manufacturing practices (GMPs) and failure to meet those standards. In particular, once a given drug batch has failed to meet release specifications due to excessive impurities, for example quality control managers must test other batches that "could have been similarly affected", FDA stresses.

Additionally, drug firms must conduct a thorough failure investigation including an assessment of causes behind out - of - specification results, documentation supporting that conclusion and descriptions of corrective actions. And, as recent warning letters bear out, the agency is interested in the investigative procedure itself - written procedures must be available for FDA review.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERThe "consistent follow - up" theme applies to crude materials, as well as finished drugs. Crude materials and recovered solvents must be tested and the results documented to assure that they fall within validated process control specifications. Quality Control managers should be prepared to present written evidence that both crude materials and recovered solvents produced in - specification finished products. FDA stressed.

Incidentally, in - process requirements for recovered solvents and crude materials must be derived from process validation studies. Another area where attention to detail plays a key role is with validation of production procedures and process controls. Retrospective validation must be based not only on finished product testing results, but must identify processing parameters like time, temperature and equipment settings.

SHAKY SOFTWARE CONTROLS IRK FDA INSPECTORS

FDA's regulation of drug firms' software, the scope of that regulation and the level of validation for software changes remain nebulous and hotly debated issues. However, uncertainty in this nascent area is not holding FDA back from issuing warning letters from practices it dislikes. In fact, compliance experts at the agency have indicated that inspector observations of common problems may be the basis for future software regulation.


Among issues now receiving inspector scrutiny are controls to ensure the integrity of all calculated data generated by lab software. Quality Control should review all laboratory computer systems to check for lapses, such as :

1. No audit trail to track the number of templates accessed in calculations.2. Inadequate password protection.3. Automatic deletion of data files after a hard copy is generated.4. No requirement to identify the user / analyst.5. No time / date stamping of spreadsheet hard copies.

Though electronic record - keeping is a hot spot for Good Manufacturing Practice (GMP) inspectors, it is not their only current priority. FDA continues to stress that drug makers must conduct thorough investigations of any and all batch failures, for instance. A crucial aspect of batch failure follow - up is retesting, which must not only determine assignable cause, but also must have documentation invalidating the out of specification results.


Inadequate sanitation practices are another GMP issue being stressed by inspectors. Contaminants found in drugs or process areas range from the microbial to the mundane, and can include items like insect debris, sunflower seeds and even fragments of latex gloves. Firms must assure that cleaning procedures are capable of removing all identified contaminants. The deviations discussed above and others were cited in a Nov. 26 warning letter to Purepac (*). A firm official says over 50% of its corrections pre - dated the letter.

TOP 10 REASONS FOR FDA RECA LLS IN THE RECENT YEARS

1. Deviations from current GMPs 6. Label mix - ups2. Subpotency 7. Stability data do not support an

expiration date.3. Dissolution failure 8. Product lacks stability4. Pyrogen test failure 9. Content uniformity requirement

failure5. Presence of foreign substance(s) 10. pH failure

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTER FDAers CLARIFY EQUIPMENT UPKEEP REQUIREMENTS

Though regular calibration of equipment is a critical inspection flash point and an area in which the inspectors have noted increasing violations drug plant workers need not calibrate all plant equipment, FDAers stress. Good Manufacturing Practice (GMP) regulations are silent as to which specific pieces of machinery are critical for calibration / maintenance purposes. An FDAer in the compliance office said "the need for calibrating a given a piece of equipment depends on its function."

What functions will inspectors focus on ? One type of equipment likely to receive attention during a GMP inspection is that devoted to measuring materials. The FDAer said that particular guideline is "self - evident". For other types of equipment, the answer is less clear - cut. For example, relevant GMP standards are interpreted by a 1978 preamble, requiring calibration for any piece of equipment affecting "product quality".

To avoid arousing inspector suspicions, drug makers should keep clear, detailed records outlining their calibration schedule for all pieces of equipment. FDA expects firms to calibrate and / or otherwise maintain their equipment according to an established schedule, the FDAer stressed. That source suggested that companies tend towards inclusiveness in determining which equipment to include in their calibration schedule.

WASHINGTON DRUG LETTERWASHINGTON DRUG LETTERHe also warned that plant records must show that a company is adhering to its own schedule for calibration and maintenance. Specifically, records should tell an inspector when a piece of equipment was last calibrated or maintained, the results and any action taken, and the date of the next scheduled check. While firms may label equipment with calibration dates at their own discretion, the FDAer cautioned that such a tag alone "should not be assumed to satisfy regulatory demands" ; documentation is required.

The source also warned firms not to confuse the use of calibration tags with a GMP requirement that major equipment be identified with a distinctive number or code recorded in batch records. The latter is intended to aid in documenting which pieces of equipment were used to make which drug batches. Finally, the FDAer said a firm should be able to justify its decision not to include a piece of equipment in its calibration / maintenance program.

FOREIGN INSPECTIONS STRESS EQUIPMENT CONTROLS

Any equipment involved in the manufacturing, processing, packaging or holding of a drug, whether it is automatic, electronic or mechanical, must be calibrated and inspected routinely to avoid violations like :


Failure to calibrate thermocoupler used to monitor temperatures of depyrogenation ovens and autoclaves.

Failure to periodically monitor chamber and surface of lyophilizers to detect presence of oil and thermal fluid.

Failure to calibrate thermometers and hygrometers used to monitor temperature and humidity, particularly in filling areas.

Regular cleaning, sanitizing and maintaining equipment to prevent contamination or malfunction should encompass such components as the air vent filters used on the formulated bulk container, autoclaves and depyrogenation oven, as well as nitrogen gas filters used on lyophilizers. Moreover, records outlining the cleaning procedures (and their validation) must be readily available for inspectors' review.

Residue limits for any fumigating agents used in production areas must be set, as well. Inspectors continue to insist on separate or well - defined areas to prevent contamination during aseptic processing or other equally effective anti - contaminant control systems. For example, the following practices will likely draw a warning letter.


1. Placing sterile siliconized stoppers inside a filling machine hopper.

2. Failing to perform integrity tests, air velocity and smoke studies for the filters supplying air to the filling areas.

3. Performing inoculation of subculture flasks and fermenters in an uncontrolled environment.

Finally, quality control must conduct a thorough evaluation before approving changes to specifications such as moisture. The above violations were noted in a FDA warning letter sent to the Swiss Serum and Vaccine Institute Berne at its facility in that city.

FORMULATION DEVELOPMENTFORMULATION DEVELOPMENT 1. The master coating formula contains a general statement allowing for

additional quantities of coating solution due to volume loss as a result of the solvents in the materials. However, there is no specified limit to what can be added. There is also no documentation to indicate that even after additional solution is incorporated that each of the five coating pans receives only the indicated total quantity of solution of …………. kg which is reflected in the formula.

2. Current master coating formulas lack adequate coating instruction in that parameters such as number of guns, distance of guns from tablet bed and distance between the guns are not specified.

3. There were no particle size specifications for the drug substance nor for the granulation after milling.

4. The firm has not adequately validated the manufacturing process for their ……… tablets. For example,

According to the coating validation logs for both validation batches, actual coating parameters such as spray rate, spray pressure, and

temperature differed from the parameters indicated in the current master coating formula used to manufacture these batches.

FORMULATION DEVELOPMENTFORMULATION DEVELOPMENTSamples for validation of the compression operation were analysed for

dissolution and content uniformity from a single sample taken only at the beginning of the compression run.

5. ….the master production record for…capsules fails to include coating

parameters such as spray rates, on/off cycles, tip size and distance from bead bed.

6. The firm has not adequately validated the manufacturing process for their

……… tablets. For example, According to the coating validation logs for both validation batches, actual

coating parameters such as spray rate, spray pressure, and temperature differed from the parameters indicated in the current master coating formula used to manufacture these batches.

Samples for validation of the compression operation were analysed for dissolution and content uniformity from a single sample taken only at the beginning of the compression run.


7. The tablet compression process has not been validated. The tablet compression study determining the hardness, thickness and friability of the product was done at ….tablets per minute. The commercial production rate is …………… tablets per minute.

8. The master coating formula contains a general statement allowing for


9. Current master coating formulas lack adequate coating instruction in that

parameters such as number of guns, distance of guns from tablet bed and distance between the guns are not specified.

10. Manufacturing process validation protocols / SOP are inadequate, they :


Do not indicate the number of drug batches per product to be validated. Do not include installation qualification studies for equipment used to

manufacture tablets and capsules. Lack a description of the equipment to be used for manufacturing and

sampling. Do not describe the sample collection method. Lack a description of length and duration of the study. Lack criteria for a successful study. Lack a statement of situations in which the manufacturing process would be

revalidated. Fail to include the worst case operating conditions for finished product

dissolution and content uniformity. Fail to specify the operating speed ranges of the tableting and

encapsulation equipment. Fail to address different speeds of tableting and encapsulation

equipments. 11. ….the procedures to be followed when handling light sensitive material are

not specified in the production formulation for ……


12. ……before approval, the manufacturing directions for the compression blend process under NDA supplement ….were changed significantly, and therefore result in the pivotal/bio-batches. The blending steps used in the commercial scale-up/validation batches differ from that used in NDA

13. NDA ………. No specific terms and / or instructions are stated in the written

procedures for different manufacturing steps of ………….. For example, it is not specified in the Master Batch Record or in the batch production records the order in which drug ingredients are added. The …………. Monograph does not specify those critical process parameters such as ………… time, initial equipment settling etc. Also the sampling size and sampling frequency are not specified.

14. The manufacturing process for ………. tablets is not validated in that :

1. There is no data justifying mixing times during granulations ; no characterization or evaluation of granules formed, no limits on mixing time including the effects if any of the over mixing, nor is there justification of blend times.


2. Particle size specifications for the drug substance were developed based on only the sizes common to the two suppliers of the drug substances

(mesh size 50, 100, 400). There is no report addressing differences in

particle size in the mix - range (mesh size 140, 270 and 325) nor their relationship to drug substance used in the biobatch.

3. There is no evaluation of the effect if any, of the optional step of adding water and of variable drying times.

15. Review of the batch records for …… tablets disclosed the following deficiencies for the granulation phase :

The batch records do not specify how the granulating solution was added.

The records do not specify whether the process reached the granulation endpoint.

There is no temperature range for the gelatin solution added during the granulation process.


16. …..documentation was not available to show that current manufacturing

processes are validated for ….. products which include validation documentation for equipment processing parameters for all stages of manufacturing. This includes lack of validation documentation for the film coating processes and manufacturing of different types and batch sizes of coating solutions.

17. In the film coating area we could not verify that each of the guns in the pans are spraying the correct amount and pattern of film coating solutions.

18. In regard to the calibration of the sprayers for the controlled film coating

equipment (the coating pans), there is no documentation available to show that the current method of using …… and not the actual processing film coating solutions, for calibrations, will give accurate results for all types of coating solutions used during manufacturing. The purpose of this calibration is to assure that the spray rates of the different film coating solutions are accurate and the reported total amounts sprayed are accurate.


19. A report, dated ……,stated: "when two coating pans were tested using the same target specification range for total amount of coating solution sprayed , there was a significant difference in the amount of coating solution applied per an which also reflected in the average weight gain per tablet." Personnel stated, corrective action to this observation would involve calibrating the sprayer with the actual processing film coating solutions, which is not currently being done.

20. Personnel stated the frequency that the firm coating operation is stopped for cleaning or replacement of the nozzles due to spray problems during batch production is not known, since it is not documented.

21. There was no documentation available regarding specifications for processing parameters that affect the manufacturing process.

22. The first three validation batches used a sample size of …… for uniformity of blend analysis. The use of 1 to 2 gram sample size does not approximate the 120 mg tablet weight of this product. These samples did not reveal the subpotency problem in the uniformity of the granulation at the end of the run in the ribbon blender scrapings which was identified in the second set of validation batches.


23. The validation data for the twin shell V blender used to blend active ingredient blends did not include the rotational speed at which the blender was run during the studies.

24. The visual inspection of stability and retention samples for color is subjective. To date, no standards are used in the visual examination for color.

25. …..ANDA field alerts are not routinely filed concerning any significant chemical, physical or other changes, deterioration, or failure to meet specifications in distributed drug product. For example, ….capsules, failed dissolution testing at the ninth month stability station, a field alert was never filed.

26. Available records indicate that the total blend volumes, based on blend densities, had not been calculated and compared to the working capacity of the blender, until the current inspection. Bulk and tap densities on the (initial) blend were not measured, and samples weren't obtained and/or saved. When bulk and tap densities were measured on a final blend sample during this inspection, and calculations performed, the data indicated that the blend volumes is approximately ….. of the blender's working capacity, per site change NDA supplement, your firm uses a different type of blender than the innovator's.


27. Blending validation studies for ….tablets appear deficient: a) Impurity profiles on the active ingredient were not addressed.

b) There were no parameters for particle size distribution of the final blends.c) Mixing speeds were not monitored.d) Sample sizes were too large to provide adequate information with respect to blend uniformity.e) The length of time bulk powder can be held in drums/totes prior to

compression or filling was not evaluated during validation studies.

28. Before approval, the manufacturing directions for the compression blend process under NDA Supplement ………. were changed significantly, and therefore result

in the pivotal / bio - batch not to be entirely representative of the current product / process. The blending steps used in the commercial scale - up / validation batches differs from that used in NDA pilot / bio - batches. Concerns with blend uniformity variability observed with development and pilot batches gave way to a "design of experiment" that resulted in the said pre - mix and mixing parameter changes. The changes in the manufacturing directions were not included in an addendum to this NDA supplement.


29. There is insufficient data to provide a high degree of assurance that the blend process is under control and fully validated. After encountering notable variability in blend uniformity test results during development and pilot batches, an experimental design study was done to identify factors contributing to this variability. The conclusions drawn from that study were not appropriately transferred to the scale - up / validation batches and justified. The rational used for assigning parameters was contradictory.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS 1. The validation studies performed on the fluid bed drying process for ……….

granulation did not include the equipment settings used on the validation batches. There is no assurance that the settings used on current batches are identical to those used on the validation batches.




sampling. Do not describe the sample collection method. Lack a description of length and duration of the study. Lack criteria for a successful study. Lack a statement of situations in which the manufacturing process would be


dissolution and content uniformity. Fail to specify the operating speed ranges of the tableting and encapsulation

equipment.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS Fail to address different speeds of tableting and encapsulation equipments, 3. Tablet compression is not validated.

There is no statistical characterization of the hardness, thickness or tablet weight of any strength of …………. Tablet. A study was developed during this inspection.

Process capability studies have not been performed and process control limits established for hardness, thickness or tablet weight. Compression is monitored every ……….. minutes against release specifications. There was no upper control and lower control limits (alert limits) for these parameters.

There are no procedures established to adjust compression force or compression rate i.e. consecutive samples trending towards the upper release specifications.

4. Products manufactured which were found to contain foreign materials were

reprocessed and/or visually inspected. There is no assurance that these corrective actions were capable of removing all identified contaminant. For example,

MANUFACTURING CONTROLSMANUFACTURING CONTROLS A tablet contained a piece of latex glove. While the amount of latex

contamination could not be identified, the batch was visually inspected and released.

5. The firm has not adequately validated the manufacturing process for their

……… tablets. For example, According to the coating validation logs for both validation batches, actual



6. The tablet compression process has not been validated. The tablet

compression study determining the hardness, thickness and friability of the product was done at ….tablets per minute. The commercial production rate is …………… tablets per minute.


7. The problem of a foreign capsule being found in this batch occurred during inspection. Inspection records for this batch do not document that the batch was reinspected after finding the foreign capsule.

8. No time frames / limitations have been established for production equipment from end of use to start of cleaning.

9. The Batch Manufacturing Record (BMR) for …… tablets, shows that the time between removal of the “dried granulation” from the drying oven until the next processing step was from …………….. until …………. (13 days). The SOP in effect at that time, titled : “Manufacturing Phase Time Limits” defined the maximum time limits between Granulation and Blending to be ………….. According to the procedure, if the time limits are “exceeded, the batch must be evaluated by Quality Assurance before proceeding to the next step in the process”. The above referenced BMR contains no documentation that the batch was evaluated subsequent to the extended storage time.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS10. Capsule validation batch ……… failed mix homogeneity and content uniformity

requirements and was rejected. No assignable cause could be identified. Drum samples were performed on three additional lots. Two lots exhibited values above acceptable criteria. Additional samples, taken from the same locations were assayed in duplicate resulting in values of ……………. The validation effort was accepted without investigation or explanation of the out - of – specification results.

11. Investigations are not initiated when capsule batches fail in - process testing requirements for weight variation. The impact of these failures on similar batches is not evaluated. For example, batch ………….., was sorted prior to packaging as an underweight capsule (less than 50%) was found during visual inspection. The sorting process rejected over 3,400 capsules that were less than 90 % filled. No investigation was conducted to determine the cause of the underweight capsules.

12. The method validation for the manufacturing process of topical products is lacking in that in - process sampling of products is not performed in a manner to verify that there are no “dead spots” in the kettles used for manufacturing. Three of the twelve samples are taken directly from the tank while the remaining nine are taken as product is removed from the kettle from the bottom orifice of the kettle.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS13. The mixing speeds indicated in the manufacturing records do no coincide with the

firm’s “Kettle Mixing Speed Guidelines”. Mixing speeds in the batch records are specified as “slow, medium, and medium - high”. The kettles monitor mixing speeds in RPMs.

14. Review of the batch records for …… tablets disclosed the following deficiencies for the granulation phase :

The batch records do not specify how the granulating solution was added. The records do not specify whether the process reached the granulation

endpoint. There is no temperature range for the gelatin solution added during the

granulation process.

15. Failure to follow Change Control Procedure for …………. Systems and Software Version Control, to provide adequate revision controls over ……….. programs, and the various source codes used in manufacturing process control systems, in that :

Several software changes were reportedly made but not properly documented. For example, several changes to status prompt messages, and changes to pan speed and spray rate deviation settings.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS The vendor version installed was designated ……….., yet after

modifications resulting from installation / operation qualification no new revision number was given.

16. Failure to conduct periodic reviews of the various computer control systems for performance, changes and configuration control in deviation of ………… per SOP. This SOP requires documented annual reviews of all system for changes and the need for requalification. Yet, according to personnel interviewed, it was totally overlooked and never put into practice.

17. ….no trend analysis is performed on any complaints.

18. ….SOP for Compression operating procedure start-up … is inadequate , in that it does not include any procedures to ensure that ,upon restart, there are no partial tablets or residues left in the machine. Firm received 3 complaints, from 3diferent pharmacies, regarding large tablets for lot ….the largest tablet returned was found to contain 128.6% of … the USP limit for this product is 107%.

19. ….the procedures to be followed when handling light sensitive material are not specified in the production formulation for….


20. …. SOP … was not followed by the Compression department supervisor for tablet press selection in that the tablet press validation guide was not reviewed in order to “verify that the type of compression process of the product to be compressed has been validated on the tablet press selected”.

21. ……SOP for compression operating procedure start-up ……… is inadequate, in that it does not include any procedures to ensure that , upon re-start, there are no partial tablets or residues left in the machine. Firm received 3 complaints, from 3 different pharmacies, regarding large tablets for lot ….. The largest tablet returned was found to contain 128.6% of ……The USP limit for this product is 107%.

22. …….Lot ……, filling "Down time" log states : "no ….H2O" and describes that filling was subsequently suspended for more than 7 hours . No documentation was maintained to explain this event, the management of the fill line during the event , or impact of the event on the product being filled.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS23. There are no SOP's or records to cover reworking of packaged tablets and capsules.

For example :

Firm's Quality Assurance Manager stated that approximately once per month a discrepancy is found between package inserts used and those remaining. This means that parts of a lot of product must have the caps removed, the inner seals broken and the product checked for the insert. No records are kept of these operations.

There are no SOP's to cover the reuse of inner seals and the procedures to use to assure they can be reused / resealed properly when checking for missing inserts in product.

24. Splices in roll labels are not checked either at the time of receipt or use to assure that the labels before and after the splices are the same. In addition, receiving procedures for incoming labels require that only one label per receiving lot be checked for "Incorrect, illegible, missing copy, UPC or design".

25. Labeled cartons are not examined for identity and conformity to the labelling specified in the master or batch production records at the time the cartons are issued for a finished product batch.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS26. There is no physical separation between the labeling lines in the off - line

labeling room. The spatial separation is not clearly defined. The staging areas for each line are not identified.

27. There was no validation for the capping machine used to apply plastic caps to

the bottles containing tablets and capsules. No torque specifications have been developed for the caps and seals used by firm on its products.

28. There was a lack of validation and specifications for the speed of the fan and

the heat of the heat gun used to "activate" the inner seals on caps used in the packaging of ………….. capsules.

29. Batch Production and Control records do not include complete information

relating to a batch. For instance, in - process laboratory results (control records) such as individual values for weights (as well as hardness, thickness, etc.) are not maintained with the batch record in the case of both tablet and capsule products. In addition, while samples are taken at the beginning, middle and end of production plus generally one or more random tests, none of these random test results are included in batch records (neither in summary sheet reports nor as individual values).

MANUFACTURING CONTROLSMANUFACTURING CONTROLS30. Ineffective training of production assembly personnel, the actual practices of

hairnetting, gowning, hand washing, glove usage and shoe covering by production assembly operators was inconsistent from work area to work area and also between operators within the same work area.

31. The manufacturing process for ……….. tablets has not been validated with respect to critical control points. A process change, to a constant increased tablet weight, was made as the previous manufacturing process failed to consistently meet pre - determined assay release specifications. There is a lack of data to support this process change, as investigations into previous failing batches lack an attributable cause.

32. There are no written procedures assigning responsibility for cleaning equipment, and describing in sufficient detail the cleaning schedules, the methods to be used, how the equipment is to be disassembled for cleaning, removal of previous batch identification, and protection of cleaned equipment prior to use.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS33. NDA ………. No specific terms and / or instructions are stated in the written

procedures for different manufacturing steps of ………….. For example, it is not specified in the Master Batch Record or in the batch production records the order in which drug ingredients are added. The …………. Monograph does not specify those critical process parameters such as ………… time, initial equipment settling etc. Also the sampling size and sampling frequency are not specified. `````````

34. Your firm's investigation into the "incorrect capsule length" as presented in the "Memo To : Batch Manufacturing Record", dated ………… is incomplete and inaccurate. There is no reference as to when or how the problem of the unlocked capsules was determined. The memorandum of investigation also does not document the fact that three different …………. encapsulators were used to "re-close" the batch

35. Firm has no written procedures to identify all instruments used during the

manufacturing process. During the manufacturing process portable instruments that require calibration or certification are used at different stages and there is no traceability of the instrument used to the batch.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS36. A large number of the production personnel could not read or understand

English, yet they were following SOP's and signing batch records that were written in English.

37. Although you maintain a calibration log of the ………… electronic label counter, it is inadequate in that the reference control roll that you use consists of a known quantity of "stranger" labels ; however, the log does not show the accuracy of the instrument by comparing the quantity of label read by the instrument against the known quantity, and also, it does not show whether the instrument detected the "stranger" label. Furthermore, it does not contain an acceptance criteria. For example, a label operator stated that when a low quantity is read by the instrument, the test is repeated until a satisfactory reading is obtained.

38. No formally written and approved SOPs mandate the evaluation of individual in - process hardness values or follow - up of out - of - specification results. In addition, hardness testing is not performed frequently enough to ensure adequate in - process control. While QA tests 10 tablets for hardness one every two hours (at minimum) and apparently also reviews individual results, production evaluates only an average of ten results hourly.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS39. Failure to count mylar labels received from the vendor or confirm vendor

counts or assure the count meets on receipt specifications. For example, label specifications for …………….. are "label count per roll cannot exceed 0.5% discrepancy" from vendor count. There is no documentation that partial rolls of labels are counted by a vendor.

40. Traceability to the labels used during labeling operation is difficult. 41. Two Raw Material Inventory Cards for ………….. were not accurate. These

inventories were not closed out in a timely manner which resulted in a delay to the start of an investigation into a …………… discrepancy for lot …………..

42. A reject level has not been established beyond which a lot of product would

not be released. It is the firm's policy to release lots of drug product, irrespective of the reject rate, as long as the "defect" may be inspected for and based on this inspection "acceptable" units are released. The following lots of product were released although inspection reports recorded the cited reject levels : 25.54%, 18.11%, 15.70%, 11.25% and 39.37%.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS43. The manufacturing process for ………. tablets is not validated in that : There is no impurity profile for bulk drug substance.

Raw data does not support the particle size of the drug substance specified by the firm and submitted to FDA.

There is no data justifying mixing times during granulations ; no characterization or evaluation of granules formed, no limits on mixing time including the effects if any of the over mixing, nor is there justification of blend times. Particle size specifications for the drug substance were developed based on only the sizes common to the two suppliers of the drug substances (mesh size 50, 100, 400). There is no report addressing differences in particle size in the mix - range (mesh size 140, 270 and 325) nor their relationship to drug substance used in the biobatch. There is no evaluation of the effect if any, of the optional step of adding water and of variable drying times.

44. Batch records are formatted so that operators record a single date for the wet

granulation mixing and drying steps, despite this process taking place over a two day period.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS45. There are no records showing bottles being blown out before filling. 46. Although access to batch formula screen editing is assigned based on user

profile levels, these are hard coded by individual parameter and were not fully verified during validation testing. There is no assurance these were all coded correctly. For instance, during a particular test of ……….. an error was found which permitted Level 2 (operators) access to edit formulas on screen. No record was made available showing correction and re-verification of the loaded software for this.

47. The validation of the (film coating) process control computer software consisted of limited functional testing, with no formal code structure testing, such as code coverage analysis and / or systematic unit testing made available. These functional tests failed to thoroughly, rigorously and consistently challenge the system / software in that sufficient valid testing of all input / output values, data structure, process variables, and control flow logic was not done. No complete and meaningful testing techniques (boundary value analysis, combination inputs, special case analysis, etc.) were employed for critical process parameter and / or control variables.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS48. The operational qualification of the ………. system were similarly inadequate in

that it consisted of limited functional testing, which failed to thoroughly and rigorously challenge the system and address worst case conditions as follows :

Test cases did not check all reasonable ……….. conditions that can cause errors. Boundary value analysis was not done at values just above and below the process parameters ranges, and did not include special condition values in all cases. The test protocol and test cases were not based on performance specification and crossed referenced to a formal requirement specification document. Test case failure or deviations were not adequately explained and followed up with corrective actions, retesting, and / or reassessment of equipment performance specifications. Test cases were not realistically based on the performance specifications of each piece of equipment.

49. Granulation room ……. has many high (30 feet) flat surfaces that are not cleanable between products to prevent cross - examination. The walls, ceiling and high ledges are cleaned only ……….. times per year.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS50. Blending studies did not evaluate particle distribution throughout the blend. A

composite sample from one lot was used for particle distribution studies.

51. The Tableting Portion of the Batch Production Record does not document the following :

The actual weights of samples of finished tablets collected as the process validation samples. That the process validation samples were collected with the tableting

press operating at parameters which yielded tablets at high and low hardness.

The actual weights of the full and partial containers of finished tablets. The actual weight of accountable loss at the end of the tableting operation. The theoretical tablet weight was used to calculate the yield for the compression stage.

52. The Investigation Report concerning the broken and dented capsules does not :

1. Include any investigation into the two lots of empty capsules that were used to encapsulate this batch.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS 2. Address any corrective action taken or planned to prevent a

recurrence.

3. The potential for this problem effecting other batches or products.

53. Documentation was not available to show that current manufacturing processes are validated for ………. products which includes validation documentation for equipment processing parameters for all stages of manufacturing. This includes lack of validation documentation for the film coating processes and manufacturing of different types and batch sizes of coating solutions.


55. According to personnel, film coating pan gauges are accurate for the measurement of ………… This could not be verified for all coating pan gauges used to manufacture products because there is no testing performed or documentation to show the accuracy of these gauges.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS56. In regard to the calibration of the sprayers for the controlled film coating

equipment (the coating pans), there is no documentation available to show that the current method of using ……… and not the actual processing film coating solutions, for calibration, will give accurate results for all types of coating solutions used during manufacturing. The purpose of this calibration is to assure that the spray rates of the different film coating solutions are accurate and the reported total amounts sprayed are accurate.

57. A report, dated …………, stated : "when two coating pans were tested using

the same target specification range for total amount of coating solution sprayed, there was a significant difference in the amount of coating solution applied per pan which was also reflected in the average weight gain per tablet". Personnel stated, corrective action to this observation would involve calibrating the sprayer with the actual processing film coating solutions, which is not currently being done.

58. Personnel stated the frequency that the film coating operation is stopped for

cleaning or replacement of the nozzles due to spray problems during batch production is not known, since it is not documented.


59. According to personnel and what we observed during a walk through in the manufacturing area ; personnel perform a 100% visual inspection. Batch production records do not contain documentation showing that this 100% inspection is being performed. The only visual inspection sampling documented on the batch production records are the results of sample sizes.

60. There is no time limit restriction specified in the CIP cleaning procedures for Liquid Manufacturing and Storage Tanks to assure that the procedure will effectively remove product residues.

61. The multiple computer systems which influence production are not validated. These computers control among other things the disposition (quarantine, release, reject) of all raw materials, weighing of all raw materials to master record specifications and tolerances, printing of labels for all raw materials for each batch, calculating yields at various stages of production, and printing various portions of batch records for each lot.


62. The first three validation batches used a sample size of ……….. for uniformity of blend analysis. The use of 1 to 2 gram sample size does not approximate the 120 mg. Tablet weight of this product. These samples did not reveal the sub-potency problem in the uniformity of the granulation at the end of the run in the ribbon blender scrapings which was identified in the second set of validation batches.

63. The validation blend uniformity test results for batch ………. Also documented

a problem with sub-potency at the end of the run which initiated a procedure to discard the tailings from the blender for the other two validation batches. However, the blender tailings were included in the granulation for batch …………. Which was packaged and commercially distributed.

64. Equipment used in determining component and in - process material weight

and adherence to specifications is not identified in Batch Production Records for all lots reviewed. For example, the following equipment is used and is not specified : scales and balances, hardness tester, moisture analyzers and calipers.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS65. There is no written definition of the more than …………. tablet defects which

production and in - process quality control inspectors monitor throughout each batch.

66. There is no documented training of production or in - process quality control

inspectors in the various tablet defects. 67. There is no record of the in - process tablet defects found by production operators

during their checks every ……….. minutes throughout compression. 68. Raw materials are stored in a "high - bay pallet" warehouse in building …….. There are no heat map studies to support monitored locations.

There has been no temperature / humidity monitoring since …….. 69. Currently the most recent scale / balance calibration documentation is inadequate

in that there is incomplete information to confirm that the equipment was checked for linearity throughout its operational range.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS70. All in-process measurement equipment is not identified in the batch records. For

example, the balance used to weigh the sample used for the loss on drying determination for lot ……………. is not identified.

71. In some cases, manufacturing procedures lack sufficient detail. For example :

a. Step …………. of the encapsulation batch record requires that the temperature and relative humidity be recorded. There is no instruction relative to the frequency of these checks during the encapsulation process and whether any remedial action is required if significant temperature or humidity deviations are observed.

b. Step …………… of the encapsulation batch record states that if capsule weights are outside the upper or lower limits then the affected capsules must be quarantined and evaluated individually for acceptable weight.

The procedure for this evaluation is not identified.

72. Equipment cleaning procedures lack sufficient detail. For example :

a. The tablet press cleaning procedure states that isopropyl alcohol should be used to wipe down the entire machine and that a suitable cleaning

agent should be used to flush / clean the punch chambers. The grade of alcohol, cleaning agent, and method of wiping is not specified.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS b. The Cleaning Procedure states that the cleaning solutions are

prepared according to their directions. Different directions are found on the product labels depending on disinfection level required.

c. Non - specific / subjective terms are used in equipment cleaning procedures. These include : 'frequent use" ; "infrequent use" ; "when applicable" ; "thorough (ly)" ;"suitable" ; "areas of concentration" ; "if appropriate" ; "hot tap water" ; "hot potable water" ; "high pressure washer" ; and "or equivalent".

73. The cleaning procedure for the ……….. tablet press was not found in the equipment use folder / log adjacent to the press. There is no explanation as to why this procedure was not available and no assurance that the press was adequately cleaned during the time period when the cleaning procedure was not available.

74. The computer system used for logging and tracking incoming raw materials in the shipping / receiving area lacks adequate security measures to prevent unauthorized changes to raw materials records.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS75. No documentation exists for review and approval for use of equipment used in

the processing of ………… tablets to insure that the equipment is operating within established limits and tolerances. e.g., tablet press, coating pan, oscillator, mill equipment.

76. Failure to evaluate and validate the impact on the final blend that the tote bin conveyer system has in terms of homogeneity. After blending, the bins are transported to the ……….. floor and attached to a duct - shoot fixture to convey the blended material to the compression rooms. These fixtures have motorized systems that (vibrate) the bins every ……. minutes to aid in (sending) the blend down to the compression machine hopper. There is no documented study that measures the effect (or non - effect) this has or if it regresses or improves blend uniformity.

77. Environmental conditions, i.e. temperature, humidity, that could affect the processing of tablets were not assessed during production / validation runs for ……………. batches. No monitoring of room conditions took place during production of these batches.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS78. One of the drying ovens has a 3 x 10 tray configuration and the other a 2 x 10

tray configuration. Samples are pulled from one top / middle / bottom tray and assayed for dryness. There has been no testing or validation to determine if there is a variance in drying through out these ovens.


80. During validation of the twin shell V blender the sampling procedure was not specified.

81. Despite considerable experience with blend uniformity problems in development and pilot batches, lesser testing and monitoring controls were established for the scale - up / validation batches. For example, no blend uniformity testing at the pre - mix step, no additional blend distribution testing, and the same number of tote bin sampling points were taken. From a practical viewpoint, taking into account the batch size increased from development to scale - up, the testing and sampling is insufficient for validation purposes. Five sample points were taken in both pilot and development batches, which used …………… bin size. Meanwhile, in the larger bin used in the scale - up batches, five sample points (top, middle and bottom) were again taken.


82. In spite of the experimental effort, one of the three blend validation batches

failed blend uniformity acceptance criteria, and the investigation did not provide conclusive scientific proof of the assumed most probable cause. The results of two of the five blend samples (the two middle points) were out - of - specification in individual point average (average of replicate injections). These original results were confirmed in a series of tests, which included reinjecting the same sample vial, re-pipeting, and re-centrifuging of the stock solution. Also, an inconclusive study was done to reportedly analyze variability of replicate sample, so two additional samples from each sample point were retested. That study, although it did show some variability of replicates, also showed low overall results. More importantly, it confirmed the two middle sample points were at the lowest range. The study was not conclusive in identifying what caused the variability, and inexplicably cancelled.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS 1. The cleaning validation protocol for the ……… fails to provide for : Additional cleaning Microbiological testing of swab samples Testing for residues of the cleaning solution The title of the individual /s responsible for performing and approving the

validation study The criteria for a successful study An indication of when revalidation will be required A description of the type of analytical equipment used That samples are collected using gauze squares instead of cotton swabs 2. Cleaning validation for …………. is incomplete in that no conclusion /

evaluation / final report was prepared. Cleaning SOP ………. referred to in the cleaning validation protocol and the protocol itself, fails to specify the cleaning solutions used and to mention the use of alcohol. The firm did not challenge the analytical method for analyzing cleaning validation samples to show that contaminants can be recovered and that testing of unclean equipment yields unacceptable results.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS 3. The exact locations for swab samples taken during cleaning validation studies are

not identified. Additionally, procedures allow for a second set of swab samples to be taken if necessary with no assurance that the same swab locations are not swabbed again.

4. Cleaning validation studies for some equipment including the dryer and tablet

presses allow for all of the swab samples collected to be combined into one combined sample and analyzed as such. For example, individual swab sites for the dryer were identified prior to cleaning validation and all the swabs were combined into one sample.

5. The firm fails to meet commitment made in NDA / ANDA applications as follows :

In spite of the firm’s commitment to perform in-process blend uniformity testing, only a composite of the blend is tested.

In spite of the firm’s commitment to perform in-process blend uniformity testing from the top, middle and bottom of the left and right of the blender, the first four lots sampled after the validation lots were sampled only from the drums.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS The required in-process test for potency on the bulk syrup prior to filling was

not performed on two lots. The ANDA commits to performing this test on all lots.

6. The firm lacks SOPs which specify the manner in which production blend samples are to be withdrawn (by technical services or Quality Assurance) and subsequently handled in the laboratory, such that the sampling and testing is consistent with commitments made in specific ANDA. For example,

Blend samples for ………… are received in the laboratory in individual bottles which represent a composite of the top, middle and bottom from individual drums. The contents of these bottles are pooled in the Quality Control Laboratory, according “to practice”. The composite is analyzed, to obtain a result which is titled, “in-process Blend Sample Data”.

7. Process validation studies for products using the fluid bed dryer have no specifications established for Loss On Drying (LOD), particle sizing, and bulk density testing of granulation.

8. The validation studies performed on the fluid bed drying process for ………. granulation did not include the equipment settings used on the validation batches. There is no assurance that the settings used on current batches are identical to those used on the validation batches.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS 9. The master coating formula contains a general statement allowing for


10. Current master coating formulas lack adequate coating instruction in that parameters such as number of guns, distance of guns from tablet bed and distance between the guns are not specified.




sampling.Do not describe the sample collection method.

Lack a description of length and duration of the study.

MANUFACTURING CONTROLSMANUFACTURING CONTROLSLack criteria for a successful study.

Lack a statement of situations in which the manufacturing process would be revalidated.

Fail to include the worst case operating conditions for finished product dissolution and content uniformity.

Fail to specify the operating speed ranges of the tableting and encapsulation equipment.

Fail to address different speeds of tableting and encapsulation equipments, 12. Tablet compression is not validated. There is no statistical characterization of the hardness, thickness or tablet

weight of any strength of …………. Tablet. A study was developed during this inspection.

Process capability studies have not been performed and process control limits established for hardness, thickness or tablet weight. Compression is monitored every ……….. minutes against release specifications. There was no upper control and lower control limits (alert limits) for these parameters.

There are no procedures established to adjust compression force or compression rate i.e. consecutive samples trending towards the upper release specifications.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS13. There is no assurance that the sampling method employed for cleaning

validation of equipment could detect low level of residuals. A non-quantitative method ………. transfer resulted in low recoveries of spiked sampled via HPLC. There is no minimum requirement for the percent recovered from spiked samples to assure adequate cleaning. For example,

During the cleaning validation of ……… capsules, 63% from spiked samples

was recovered. During the cleaning validation of ………… capsules, 89% from spiked samples

was recovered. 14. Products manufactured which were found to contain foreign materials were

reprocessed and/or visually inspected. There is no assurance that these corrective actions were capable of removing all identified contaminant. For example,

A tablet contained a piece of latex glove. While the amount of latex contamination could not be identified, the batch was visually inspected and released.


15. The firm has not adequately validated the manufacturing process for their ……… tablets. For example,

According to the coating validation logs for both validation batches, actual



16. The tablet compression process has not been validated. The tablet

compression study determining the hardness, thickness and friability of the product was done at ….tablets per minute. The commercial production rate is …………… tablets per minute.

17. The validation data for the twin shell V blender used to blend bulk active

ingredients did not include the rotational speed at which the blender was run during the studies.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS18. Validation - The firm failed to follow their validation protocol in several areas.

Examples include :

Protocol calls for 10 x 50 g (500g) samples from final blend. Actual sample size was recorded as 550g and does not reflect individual subsamples.

The batch record does not reflect that sample was collected for angle of repose and density. Laboratory records reflect these analyses were performed.


20. The investigation into the acquisition and release of aluminium stearate of the wrong grade obtained from an unapproved source failed to identify that the wrong grade of material was ordered from the vendor. Further, the evaluations of other materials to identify other sourcing / grade problems was not documented and SOPs for the purchasing of raw materials did not include a requirement to reference testing standards.

21. Product performance was not evaluated with respect to the use of alternatively sourced excipient in the production of …… tablets. Subsequent batches had marginal dissolution results which were attributed to the use of this raw material.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS22. Preservative effectiveness testing is not performed as part of the stability

program. In addition, the finished product release specifications are inadequate, in that, there is no quantitative testing performed for determination of…… levels.

23. Failure to follow Change Control Procedure for …… Systems and Software Version Control to provide adequate revision controls over ……….. programs, and the various source codes used in manufacturing process control systems, in that :

Several software changes were reportedly made but not properly documented. For example, several changes to status prompt messages, and changes to pan speed and spray rate deviation settings.

The vendor version installed was designated …… yet after modifications resulting from installation / operation qualification no new revision number was given.

24. Failure to conduct periodic reviews of the various computer control systems for peformance, changes, and configuration control in deviation of ………… per SOP. This SOP requires documented annual reviews of all system for changes and the need for requalification. Yet, according to personnel interviewed, it was totally overlooked and never put into practice.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS25. The problem of a foreign capsule being found in this batch occurred during

inspection. Inspection records for this batch do not document that the batch was reinspected after finding the foreign capsule.

26. The Validity Assessment Report was inadequate in that :

The auditors failed to adequately support some of their conclusive statements. For example, the drug substance ………… was erroneously described by the auditors as having changed from unmilled to milled : the process validation was evaluated as satisfactory without noticing that the protocol was approved after the validation lots were completed.

27. The Agency was not notified in accordance with NDA field alert reporting requirements when information concerning physical change in the distributed drug product or failure of the distributed batches to meet the assay specifications established in the application were confirmed.

28. Firm has no data to show worst case conditions for the cleaning validation of the Fluid Bed Dryer performed for …………. process verification. Swabbing was performed on general contact areas without taking into consideration areas such as edges and crevices of windows and sampling ports of the bowl of the Fluid Bed Dryer.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS29. Protocol …………….., Validation of the Cleaning Procedures lists an

acceptance criteria for tested materials recovered, shall not exceed …………. mcg / cm2. There is no data to justify this limit.

30. No time frames / limitations have been established for production equipment from end of use to start of cleaning.

31. The returned goods procedure is inadequate in that :

a. The log of all materials received in the warehouse (“docklog”) is not audited against the “returns log” to assure all returns are captured.

b. The returns log is not audited against the ultimate disposition of the return.

c. There is no traceability of materials identified to be destroyed and a specific destruction order.

32. The training of employees is deficient in that employees do not always notify

their supervisors about defects or problems. For example, a malfunctioning meter on a UV light located on the water system was not fixed for six weeks because the supervisor was not notified, and a second malfunctioning meter was not fixed for five weeks.


33. Training records for employees often fail to provide necessary information, e.g. length of session(s) and the specific topic(s) which were covered. Some records list only one or more SOP numbers as subject matter ; and there is typically no record of the length of the training session.

34. The “Guidelines For Defect Classification” in SOP …………. indicates that

“Foreign matter such as metal particles, black specks” are to be classified as “Critical Defects” and therefore have an Acceptable Quality Level (AQL) of 0%. This procedure contains no provisions for the continued retesting lots which fail the assigned limits of AQL.

35. The Batch Manufacturing Record (BMR) for …… tablets, shows that the time

between removal of the “dried granulation” from the drying oven until the next processing step was from …………….. until …………. (13 days). The SOP in effect at that time, titled : “Manufacturing Phase Time Limits” defined the maximum time limits between Granulation and Blending to be ………….. According to the procedure, if the time limits are “exceeded, the batch must be evaluated by Quality Assurance before proceeding to the next step in the process”. The above referenced BMR contains no documentation that the batch was evaluated subsequent to the extended storage time.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS36. The current protocol for validating the manufacturing for ……… does not state

the process parameters that would be covered by the validation. For example, it does not require a comparison between bio - availability batches and validation batches.

37. Capsule validation batch ……… failed mix homogeneity and content

uniformity requirements and was rejected. No assignable cause could be identified. Drum samples were performed on three additional lots. Two lots exhibited values above acceptable criteria. Additional samples, taken from the same locations were assayed in duplicate resulting in values of ……………. The validation effort was accepted without investigation or explanation of the out - of - specification results.

38. Investigations are not initiated when capsule batches fail in - process testing

requirements for weight variation. The impact of these failures on similar batches is not evaluated. For example, batch ………….., was sorted prior to packaging as an underweight capsule (less than 50%) was found during visual inspection. The sorting process rejected over 3,400 capsules that were less than 90 % filled. No investigation was conducted to determine the cause of the underweight capsules.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS39. The method validation for the manufacturing process of topical products is

lacking in that in - process sampling of products is not performed in a manner to verify that there are no “dead spots” in the kettles used for manufacturing. Three of the twelve samples are taken directly from the tank while the remaining nine are taken as product is removed from the kettle from the bottom orifice of the kettle.

40. The mixing speeds indicated in the manufacturing records do no coincide with

the firm’s “Kettle Mixing Speed Guidelines”. Mixing speeds in the batch records are specified as “slow, medium, and medium - high”. The kettles monitor mixing speeds in RPMs.

41. Review of the batch records for …… tablets disclosed the following

deficiencies for the granulation phase :

a. The batch records do not specify how the granulating solution was added.b. The records do not specify whether the process reached the granulation endpoint.c. There is no temperature range for the gelatin solution added during the granulation process.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS42. Failure to follow Change Control Procedure for …………. Systems and

Software Version Control, to provide adequate revision controls over ……….. programs, and the various source codes used in manufacturing process control systems, in that :

a. Several software changes were reportedly made but not properly

documented. For example, several changes to status prompt messages, and changes to pan speed and spray rate deviation settings.b. The vendor version installed was designated ……….., yet after modifications resulting from installation / operation qualification no new revision number was given.

43. Failure to conduct periodic reviews of the various computer control systems

for performance, changes and configuration control in deviation of ………… per SOP. This SOP requires documented annual reviews of all system for changes and the need for requalification. Yet, according to personnel interviewed, it was totally overlooked and never put into practice.

44. ….no trend analysis is performed on any complaints.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS45. ….SOP for Compression operating procedure start-up … is inadequate , in

that it does not include any procedures to ensure that ,upon restart, there are no partial tablets or residues left in the machine. Firm received 3 complaints, from 3diferent pharmacies, regarding large tablets for lot ….the largest tablet returned was found to contain 128.6% of … the USP limit for this product is 107%

46. ….the procedures to be followed when handling light sensitive material are

not specified in the production formulation for…. 47. ….SOP … was not followed by the Compression department supervisor for

tablet press selection in that the tablet press validation guide was not reviewed in order to “verify that the type of compression process of the product to be compressed has been validated on the tablet press selected”.

48. ……SOP for compression operating procedure start-up ………is inadequate ,

in that it does not include any procedures to ensure that , upon re-start, there are no partial tablets or residues left in the machine. Firm received 3 complaints, from 3 different pharmacies, regarding large tablets for lot ….. The largest tablet returned was found to contain 128.6% of ……The USP limit for this product is 107%.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS49. …….Lot ……, filling "Down time" log states : "no ….H2O" and describes that

filling was subsequently suspended for more than 7 hours . No documentation was maintained to explain this event, the management of the fill line during the event , or impact of the event on the product being filled.

50. There are no SOP's or records to cover reworking of packaged tablets and capsules. For example :

a. Firm's Quality Assurance Manager stated that approximately once per month a discrepancy is found between package inserts used and those remaining. This means that parts of a lot of product must have the caps removed, the inner seals broken and the product checked for the insert. No records are kept of these operations.

b. There are no SOP's to cover the reuse of inner seals and the procedures to use to assure they can be reused / resealed properly when checking for missing inserts in product.

51. Splices in roll labels are not checked either at the time of receipt or use to assure that the labels before and after the splices are the same. In addition, receiving procedures for incoming labels require that only one label per receiving lot be checked for "Incorrect, illegible, missing copy, UPC or design".


52. Labeled cartons are not examined for identity and conformity to the labelling specified in the master or batch production records at the time the cartons are issued for a finished product batch.

53. There is no physical separation between the labeling lines in the off - line labeling room. The spatial separation is not clearly defined. The staging areas for each line are not identified.

54. There was no validation for the capping machine used to apply plastic caps to the bottles containing tablets and capsules. No torque specifications have been developed for the caps and seals used by firm on its products.

55. There was a lack of validation and specifications for the speed of the fan and the heat of the heat gun used to "activate" the inner seals on caps used in the packaging of ………….. capsules.


56. Batch Production and Control records do not include complete information relating to a batch. For instance, in - process laboratory results (control records) such as individual values for weights (as well as hardness, thickness, etc.) are not maintained with the batch record in the case of both tablet and capsule products. In addition, while samples are taken at the beginning, middle and end of production plus generally one or more random tests, none of these random test results are included in batch records (neither in summary sheet reports nor as individual values).

57. Ineffective training of production assembly personnel, the actual practices of

hairnetting, gowning, hand washing, glove usage and shoe covering by production assembly operators was inconsistent from work area to work area and also between operators within the same work area.

58. The manufacturing process for ……….. tablets has not been validated with

respect to critical control points. A process change, to a constant increased tablet weight, was made as the previous manufacturing process failed to consistently meet pre - determined assay release specifications. There is a lack of data to support this process change, as investigations into previous failing batches lack an attributable cause.


59. There are no written procedures assigning responsibility for cleaning equipment, and describing in sufficient detail the cleaning schedules, the methods to be used, how the equipment is to be disassembled for cleaning, removal of previous batch identification, and protection of cleaned equipment prior to use.

60. NDA ………. No specific terms and / or instructions are stated in the written

procedures for different manufacturing steps of ………….. For example, it is not specified in the Master Batch Record or in the batch production records the order in which drug ingredients are added. The …………. Monograph does not specify those critical process parameters such as ………… time, initial equipment settling etc. Also the sampling size and sampling frequency are not specified. `````````

61. Your firm's investigation into the "incorrect capsule length" as presented in

the "Memo To : Batch Manufacturing Record", dated ………… is incomplete and inaccurate. There is no reference as to when or how the problem of the unlocked capsules was determined. The memorandum of investigation also does not document the fact that three different …………. encapsulators were used to "re-close" the batch.


62. Firm has no written procedures to identify all instruments used during the manufacturing process. During the manufacturing process portable instruments that require calibration or certification are used at different stages and thereis no traceability of the instrument used to the batch.

63. A large number of the production personnel could not read or understand English, yet they were following SOP's and signing batch records that were written in English.

64. Although you maintain a calibration log of the ………… electronic label counter, it is inadequate in that the reference control roll that you use consists of a known quantity of "stranger" labels ; however, the log does not show the accuracy of the instrument by comparing the quantity of label read by the instrument against the known quantity, and also, it does not show whether the instrument detected the "stranger" label. Furthermore, it does not contain an acceptance criteria. For example, a label operator stated that when a low quantity is read by the instrument, the test is repeated until a satisfactory reading is obtained.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS65. No formally written and approved SOPs mandate the evaluation of individual

in - process hardness values or follow - up of out - of - specification results. In addition, hardness testing is not performed frequently enough to ensure adequate in - process control. While QA tests 10 tablets for hardness one every two hours (at minimum) and apparently also reviews individual results, production evaluates only an average of ten results hourly.

66. Failure to count mylar labels received from the vendor or confirm vendor counts or assure the count meets on receipt specifications. For example, label specifications for …………….. are "label count per roll cannot exceed 0.5% discrepancy" from vendor count. There is no documentation that partial rolls of labels are counted by a vendor.

67. Traceability to the labels used during labeling operation is difficult.

68. Two Raw Material Inventory Cards for ………….. were not accurate. These inventories were not closed out in a timely manner which resulted in a delay to the start of an investigation into a …………… discrepancy for lot …………..

MANUFACTURING CONTROLSMANUFACTURING CONTROLS69. A reject level has not been established beyond which a lot of product would not

be released. It is the firm's policy to release lots of drug product, irrespective of the reject rate, as long as the "defect" may be inspected for and based on this inspection "acceptable" units are released. The following lots of product were released although inspection reports recorded the cited reject levels : 25.54%, 18.11%, 15.70%, 11.25% and 39.37%.

70. The manufacturing process for ………. tablets is not validated in that :

1. There is no impurity profile for bulk drug substance.2. Raw data does not support the particle size of the drug substance specified by the firm and submitted to FDA.3. There is no data justifying mixing times during granulations ; no characterization or evaluation of granules formed, no limits on mixing time including the effects if any of the over mixing, nor is there justification of blend times.4. Particle size specifications for the drug substance were developed based on only the sizes common to the two suppliers of the drug substances

(mesh size 50, 100, 400). There is no report addressing differences in particle size in the mix - range (mesh size 140, 270 and 325) nor their relationship to drug substance used in the biobatch.

5. There is no evaluation of the effect if any, of the optional step of adding water and of variable drying times.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS71. Batch records are formatted so that operators record a single date for the wet

granulation mixing and drying steps, despite this process taking place over a two day period.

72. There are no records showing bottles being blown out before filling.

73. Although access to batch formula screen editing is assigned based on user profile levels, these are hard coded by individual parameter and were not fully verified during validation testing. There is no assurance these were all coded correctly. For instance, during a particular test of ……….. an error was found which permitted Level 2 (operators) access to edit formulas on screen. No record was made available showing correction and re-verification of the loaded software for this.

74. The validation of the (film coating) process control computer software consisted of limited functional testing, with no formal code structure testing, such as code coverage analysis and / or systematic unit testing made available. These functional tests failed to thoroughly, rigorously and consistently challenge the system / software in that sufficient valid testing of all input / output values, data structure, process variables, and control flow logic was not done. No complete and meaningful testing techniques (boundary value analysis, combination inputs, special case analysis, etc.) were employed for critical process parameter and / or control variables.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS75. The operational qualification of the ………. system were similarly inadequate

in that it consisted of limited functional testing, which failed to thoroughly and rigorously challenge the system and address worst case conditions as follows :

1. Test cases did not check all reasonable ……….. conditions that can cause errors.2. Boundary value analysis was not done at values just above and below the process parameters ranges, and did not include special condition values in all cases.3. The test protocol and test cases were not based on performance specification and crossed referenced to a formal requirement specification document.4. Test case failure or deviations were not adequately explained and followed up with corrective actions, retesting, and / or reassessment of equipment performance specifications.5. Test cases were not realistically based on the performance specifications of each piece of equipment.

76. Granulation room ……. Has many high (30 feet) flat surfaces that are not cleanable between products to prevent cross - examination. The walls, ceiling and high ledges are cleaned only ……….. times per year.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS77. Blending studies did not evaluate particle distribution throughout the blend. A

composite sample from one lot was used for particle distribution studies.

78. The Tableting Portion of the Batch Production Record does not document the following :

1. The actual weights of samples of finished tablets collected as the process validation samples.2. That the process validation samples were collected with the tableting

press operating at parameters which yielded tablets at high and low hardness.

3. The actual weights of the full and partial containers of finished tablets.4. The actual weight of accountable loss at the end of the tableting operation. The theoretical tablet weight was used to calculate the yield for the compression stage.

79. The Investigation Report concerning the broken and dented capsules does not :

1. Include any investigation into the two lots of empty capsules which were used to encapsulate this batch.2. Address any corrective action taken or planned to prevent a recurrence.3. The potential for this problem effecting other batches or products.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS80. Documentation was not available to show that current manufacturing

processes are validated for ………. products which includes validation documentation for equipment processing parameters for all stages of manufacturing. This includes lack of validation documentation for the film coating processes and manufacturing of different types and batch sizes of coating solutions.


82. According to personnel, film coating pan gauges are accurate for the measurement of ………… This could not be verified for all coating pan gauges used to manufacture products because there is no testing performed or documentation to show the accuracy of these gauges.

83. In regard to the calibration of the sprayers for the controlled film coating equipment (the coating pans), there is no documentation available to show that the current method of using ……… and not the actual processing film coating solutions, for calibration, will give accurate results for all types of coating solutions used during manufacturing. The purpose of this calibration is to assure that the spray rates of the different film coating solutions are accurate and the reported total amounts sprayed are accurate.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS84. A report, dated …………, stated : "when two coating pans were tested using

the same target specification range for total amount of coating solution sprayed, there was a significant difference in the amount of coating solution applied per pan which was also reflected in the average weight gain per tablet". Personnel stated, corrective action to this observation would involve calibrating the sprayer with the actual processing film coating solutions, which is not currently being done.

85. Personnel stated the frequency that the film coating operation is stopped for

cleaning or replacement of the nozzles due to spray problems during batch production is not known, since it is not documented.

86. According to personnel and what we observed during a walk through in the

manufacturing area ; personnel perform a 100% visual inspection. Batch production records do not contain documentation showing that this 100% inspection is being performed. The only visual inspection sampling documented on the batch production records are the results of sample sizes.

87. There is no time limit restriction specified in the CIP cleaning procedures for

Liquid Manufacturing and Storage Tanks to assure that the procedure will effectively remove product residues.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS88. The multiple computer systems which influence production are not validated.

These computers control among other things the disposition (quarantine, release, reject) of all raw materials, weighing of all raw materials to master record specifications and tolerances, printing of labels for all raw materials for each batch, calculating yields at various stages of production, and printing various portions of batch records for each lot.

89. The first three validation batches used a sample size of ……….. for uniformity of blend analysis. The use of 1 to 2 gram sample size does not approximate the 120 mg. Tablet weight of this product. These samples did not reveal the sub-potency problem in the uniformity of the granulation at the end of the run in the ribbon blender scrapings which was identified in the second set of validation batches.

90. The validation blend uniformity test results for batch ………. Also documented a problem with sub-potency at the end of the run which initiated a procedure to discard the tailings from the blender for the other two validation batches. However, the blender tailings were included in the granulation for batch …………. Which was packaged and commercially distributed.

91. Equipment used in determining component and in - process material weight and adherence to specifications is not identified in Batch Production Records for all lots reviewed. For example, the following equipment is used and is not specified : scales and balances, hardness tester, moisture analyzers and calipers.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS92. There is no written definition of the more than …………. tablet defects which

production and in - process quality control inspectors monitor throughout each batch.

93. There is no documented training of production or in - process quality control

inspectors in the various tablet defects. 94. There is no record of the in - process tablet defects found by production

operators during their checks every ……….. minutes throughout compression. 95. Raw materials are stored in a "high - bay pallet" warehouse in building ……..

1. There are no heat map studies to support monitored locations.2. There has been no temperature / humidity monitoring since ……..

96. Currently the most recent scale / balance calibration documentation is

inadequate in that there is incomplete information to confirm that the equipment was checked for linearity throughout its operational range.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS97. All in - process measurement equipment is not identified in the batch records.

For example, the balance used to weigh the sample used for the loss on drying determination for lot ……………. is not identified.

98. In some cases, manufacturing procedures lack sufficient detail. For example :

a. Step …………. of the encapsulation batch record requires that the temperature and relative humidity be recorded. There is no instruction relative to the frequency of these checks during the encapsulation process and whether any remedial action is required if significant temperature or humidity deviations are observed.b. Step …………… of the encapsulation batch record states that if capsule weights are outside the upper or lower limits then the affected capsules must be quarantined and evaluated individually for acceptable weight. The procedure for this evaluation is not identified.

99. Equipment cleaning procedures lack sufficient detail. For example :

a. The tablet press cleaning procedure states that isopropyl alcohol should be used to wipe down the entire machine and that a suitable cleaning agent should be used to flush / clean the punch chambers. The grade of alcohol, cleaning agent, and method of wiping is not specified

MANUFACTURING CONTROLSMANUFACTURING CONTROLSb. The Cleaning Procedure states that the cleaning solutions are prepared according to their directions. Different directions are found on the product labels depending on disinfection level required.c. Non - specific / subjective terms are used in equipment cleaning procedures. These include : 'frequent use" ; "infrequent use" ; "when applicable" ; "thorough(ly)" ;"suitable" ; "areas of concentration" ; "if appropriate" ; "hot tap water" ; "hot potable water" ; "high pressure washer" ; and "or equivalent".

100. The cleaning procedure for the ……….. tablet press was not found in the equipment use folder / log adjacent to the press. There is no explanation as to why this procedure was not available and no assurance that the press was adequately cleaned during the time period when the cleaning procedure was not available.

101. The computer system used for logging and tracking incoming raw materials in the shipping / receiving area lacks adequate security measures to prevent unauthorized changes to raw materials records.

102. No documentation exists for review and approval for use of equipment used in the processing of ………… tablets to insure that the equipment is operating within established limits and tolerances. e.g., tablet press, coating pan, oscillator, mill equipment.

MANUFACTURING CONTROLSMANUFACTURING CONTROLS103. Failure to evaluate and validate the impact on the final blend that the tote bin

conveyer system has in terms of homogeneity. After blending, the bins are transported to the ……….. floor and attached to a duct - shoot fixture to convey the blended material to the compression rooms. These fixtures have motorized systems that (vibrate) the bins every ……. minutes to aid in (sending) the blend down to the compression machine hopper. There is no documented study that measures the effect (or non - effect) this has or if it regresses or improves blend uniformity.

104. Environmental conditions, i.e. temperature, humidity, that could affect the processing of tablets were not assessed during production / validation runs for ……………. batches. No monitoring of room conditions took place during production of these batches.

105. One of the drying ovens has a 3 x 10 tray configuration and the other a 2 x 10 tray configuration. Samples are pulled from one top / middle / bottom tray and assayed for dryness. There has been no testing or validation to determine if there is a variance in drying through out these ovens.



107. During validation of the twin shell V blender the sampling procedure was not specified.

108. Despite considerable experience with blend uniformity problems in development and pilot batches, lesser testing and monitoring controls were established for the scale - up / validation batches. For example, no blend uniformity testing at the pre - mix step, no additional blend distribution testing, and the same number of tote bin sampling points were taken. From a practical viewpoint, taking into account the batch size increased from development to scale - up, the testing and sampling is insufficient for validation purposes. Five sample points were taken in both pilot and development batches, which used …………… bin size. Meanwhile, in the larger bin used in the scale - up batches, five sample points (top, middle and bottom) were again taken.


109. In spite of the experimental effort, one of the three blend validation batches failed blend uniformity acceptance criteria, and the investigation did not provide conclusive scientific proof of the assumed most probable cause. The results of two of the five blend samples (the two middle points) were out - of - specification in individual point average (average of replicate injections). These original results were confirmed in a series of tests, which included reinjecting the same sample vial, re-pipeting, and re-centrifuging of the stock solution. Also, an inconclusive study was done to reportedly analyze variability of replicate sample, so two additional samples from each sample point were retested. That study, although it did show some variability of replicates, also showed low overall results. More importantly, it confirmed the two middle sample points were at the lowest range. The study was not conclusive in identifying what caused the variability, and inexplicably cancelled.


110. …Current written procedures do not assure that equipment is consistently cleaned the same as it was during cleaning validation studies. For example

The minimum hot city water rinse used to clean filling line… during validation studies was … written procedure allows a minimum hot water rinse of …

The data collection sheet show that holding tanks were manually scrubbed with a scotch bright sponge after compounding. Written procedure does not require scrubbing of tanks. The procedure states scrubbing may be done when “deemed necessary”.

The data collection sheet for this validation study show that compounding and holding tanks were manually scrubbed using soft sponges and/or stainless sponges after compounding of … the compounding tanks were scrubbed for up to … minutes.written procedure states only that manual scrubbing may be required. It does not require the scrubbing and does not specify what to use or how. Long to scrub the tank.

QUALITY ASSURANCEQUALITY ASSURANCE

1. The cleaning validation protocol for the ……… fails to provide for : Additional cleaning Microbiological testing of swab samples Testing for residues of the cleaning solution The title of the individual /s responsible for performing and approving the



QUALITY ASSURANCEQUALITY ASSURANCE 3. The exact locations for swab samples taken during cleaning validation studies

are not identified. Additionally, procedures allow for a second set of swab samples to be taken if necessary with no assurance that the same swab locations are not swabbed again.

4. Cleaning validation studies for some equipment including the dryer and tablet


5. Manufacturing process validation protocols / SOP are inadequate, they : Do not indicate the number of drug batches per product to be validated. Do not include installation qualification studies for equipment used to


sampling.Do not describe the sample collection method. Lack a description of length and duration of the study.

QUALITY ASSURANCEQUALITY ASSURANCE Lack criteria for a successful study. Lack a statement of situations in which the manufacturing process would be


dissolution and content uniformity. Fail to specify the operating speed ranges of the tableting and

encapsulation equipment. Fail to address different speeds of tableting and encapsulation

equipments, 6. Some cleaning validation studies conducted on various tableted products are

incomplete. For example : The HPLC testing of rinse and swab samples detected small amounts of

residual .……. after cleaning in several pieces of manufacturing equipment. No calculation was performed to determine whether the cumulative effect of ………. exceeded the limit of 2 ppm.

The cleaning validation study performed on ….. has no written conclusion or signatures of review and approval by senior management.

QUALITY ASSURANCEQUALITY ASSURANCE 7. The cleaning validation protocol for the ……… fails to provide for : Additional cleaning Microbiological testing of swab samples Testing for residues of the cleaning solution The title of the individual /s responsible for performing and approving the



QUALITY ASSURANCEQUALITY ASSURANCE 9. The Validity Assessment Report was inadequate in that :

The auditors failed to adequately support some of their conclusive statements. For example, the drug substance ………… was erroneously described by the auditors as having changed from unmilled to milled : the process validation was evaluated as satisfactory without noticing that the protocol was approved after the validation lots were completed.


11. Firm has no data to show worst case conditions for the cleaning validation of the Fluid Bed Dryer performed for …………. process verification. Swabbing was performed on general contact areas without taking into consideration areas such as edges and crevices of windows and sampling ports of the bowl of the Fluid Bed Dryer.

QUALITY ASSURANCEQUALITY ASSURANCE12. The returned goods procedure is inadequate in that : a. The log of all materials received in the warehouse (“docklog”) is not

audited against the “returns log” to assure all returns are captured.b. The returns log is not audited against the ultimate disposition of the

return.c. There is no traceability of materials identified to be destroyed and a

specific destruction order. 13. Training records for employees often fail to provide necessary information,

e.g. length of session(s) and the specific topic(s) which were covered. Some records list only one or more SOP numbers as subject matter ; and there is typically no record of the length of the training session.

14. The “Guidelines For Defect Classification” in SOP …………. indicates that

“Foreign matter such as metal particles, black specks” are to be classified as “Critical Defects” and therefore have an Acceptable Quality Level (AQL) of 0%. This procedure contains no provisions for the continued retesting lots which fail the assigned limits of AQL.

QUALITY ASSURANCEQUALITY ASSURANCE15. Protocol …………….., Validation of the Cleaning Procedures lists an acceptance

criteria for tested materials recovered, shall not exceed …………. mcg / cm2. There is no data to justify this limit.

16. The validation data for the twin shell V blender used to blend bulk active ingredients did not include the rotational speed at which the blender was run during the studies.

17. The exact locations for swab samples taken during cleaning validation studies are not identified. Additionally, procedures allow for a second set of swab samples to be taken if necessary with no assurance that the same swab locations are not swabbed again.



QUALITY ASSURANCEQUALITY ASSURANCE20. Validation - The firm failed to follow their validation protocol in several areas.

Examples include :

Protocol calls for 10 x 50 g (500g) samples from final blend. Actual sample size was recorded as 550g and does not reflect individual subsamples.

The batch record does not reflect that sample was collected for angle of repose and density. Laboratory records reflect these analyses were performed.



23. Product performance was not evaluated with respect to the use of alternatively sourced excipient in the production of …… tablets. Subsequent batches had marginal dissolution results which were attributed to the use of this raw material.

QUALITY ASSURANCEQUALITY ASSURANCE24. Cleaning validation studies for some equipment including the dryer and tablet


25. Equipment cleaning validation consisted of only testing purified water rinses

for pH and conductivity. It was not tested for chemical cleaning agents or product.

26. There were no written methods for cleaning of active ingredients

/intermediates from the processing equipment. Cleaning methods in use were not validated, as evidenced by repeated boil outs and failure of residue limits. Residues have not been identified.

27. The cleaning validation protocol does not address time frames for cleaning. 28. Cleaning procedures for equipment used in the manufacture of product ……

have not been validated in that cleaning and testing must be repeated many times before a negative result is obtained.

QUALITY ASSURANCEQUALITY ASSURANCE29. The firm fails to meet commitment made in NDA / ANDA applications as

follows :

In spite of the firm’s commitment to perform in-process blend uniformity testing, only a composite of the blend is tested.

In spite of the firm’s commitment to perform in-process blend uniformity testing from the top, middle and bottom of the left and right of the blender, the first four lots sampled after the validation lots were sampled only from the drums.

The required in-process test for potency on the bulk syrup prior to filling was not performed on two lots. The ANDA commits to performing this test on all lots.

30. The validation of fill room ……….. found that the velocities at the HEPA filter face did not meet specifications in the Class 100 area. The velocities were later corrected, but air flow patterns and laminarity tests were not repeated after the filters were adjusted.

31. Air velocities within the Class 100 area of the fill rooms are not taken at work height, that is the height at which the vials are filled and stoppered. The velocities, which are checked semi - annually, are taken six inches from the face of the HEPA filters.

QUALITY ASSURANCEQUALITY ASSURANCE32. The firm’s procedure : ..… entitled, “Failure Investigation Policy” is deficient in

that it does not address critical system failures. For example : a. The WFI System lost circulation and temperature [twice] for the same

reoccurring reason. On … two WFI drops reached alert levels yet there is documented “verbal” release of the system even though maintenance was still working on the system. There is no documentation of flushing of the system before its release on ……

b. 2 leaking valves were replaced 33. ……….. The entire water system has not been validated. For example, water

from the Reverse Osmosis (RO) storage tank is stored in a Feed Tank and pumped to the still. The water is ambient and static in the feed tank, booster pump and a portion of pipe leading to the still. This static portion of the water system from the RO storage tank to the still has never been validated.

34. Failure to follow Change Control Procedure for …………. Systems and


QUALITY ASSURANCEQUALITY ASSURANCEa. Several software changes were reportedly made but not properly documented. For example, several changes to status prompt messages, and changes to pan speed and spray rate deviation settings.b. The vendor version installed was designated ……….., yet after modifications resulting from installation / operation qualification no new revision number was given.


36. There is inadequate data to demonstrate that autoclave cycles for this terminally sterilized product have been validated. Three maximum load validation studies were conducted for the purpose of determining the autoclave’s cold spots for the placement of controlling thermocouples during routine production. During validation studies, one out of three cycles (for each size) resulted in high F0 valued in areas of the autoclave, which were subsequently deemed as the autoclave’s “cold spots”. Controlling thermocouples have since been placed in only one of the two areas of the autoclave found cold during the three cycles.

QUALITY ASSURANCEQUALITY ASSURANCE37. ….failure to accurately record all down time resulting from process alarms and

system breakdown. The only means of documenting the corrective actions to processing problems is a downtime log, but this log is not being filled out consistently and is not formally audited and verified by the quality assurance unit.

38. ….SOP ….. entitled; "Internal auditing" was used to perform the audits conducted …(2 years). It is deficient in that it does not include auditing all systems such as computer validations, change control systems and water systems.

QUALITY CONTROLQUALITY CONTROL 1. Some cleaning validation studies conducted on various tableted products are

incomplete. For example : a. The HPLC testing of rinse and swab samples detected small

amounts of residual .……. after cleaning in several pieces of manufacturing equipment. No calculation was performed to determine whether the cumulative effect of ………. exceeded the limit of 2 ppm.

b. The HPLC testing of rinse samples detected an unknown, “extra” peak at retention time of ………. There is no established limit for unknown HPLC peaks during cleaning effectiveness studies. There was no investigation to determine the identity of this peak, or its potential significance in product or degradant residue testing,.

2. There is no established limit for unknown HPLC peaks found during cleaning

effectiveness studies. In addition, no attempt has been made to identify these unknown HPLC peaks.

QUALITY CONTROLQUALITY CONTROL 3. The cleaning validation protocol for the ……… fails to provide for :

a. Additional cleaningb. Microbiological testing of swab samplesc. Testing for residues of the cleaning solutiond. The criteria for a successful studye. A description of the type of analytical equipment usedf. That samples are collected using gauze squares instead of cotton swabs

4. The firm did not challenge the analytical method for analyzing cleaning validation samples to show that contaminants can be recovered and that testing of unclean equipment yields unacceptable results.

5. The exact locations for swab samples taken during cleaning validation studies are not identified. Additionally, procedures allow for a second set of swab samples to be taken if necessary with no assurance that the same swab locations are not swabbed again.

6. Cleaning validation studies for some equipment including the dryer and tablet resses allow for all of the individual swab samples collected to be combined into one combined sample and analyzed as such.

QUALITY CONTROLQUALITY CONTROL 7. Protocol …………….., Validation of the Cleaning Procedures lists an

acceptance criteria for tested materials recovered, shall not exceed …………. mcg / cm2. There is no data to justify this limit.

8. The firm fails to meet commitment made in NDA / ANDA applications as follows :

a. In spite of the firm’s commitment to perform in-process blend uniformity testing, only a composite of the blend is tested.

b. In spite of the firm’s commitment to perform in-process blend uniformity testing from the top, middle and bottom of the left and right of the blender, the first four lots sampled after the validation lots were sampled only from the drums.

c. The required in-process test for potency on the bulk syrup prior to filling was not performed on two lots. The ANDA commits to performing this test on all lots.


10. Process validation studies for products using the fluid bed dryer have no specifications established for Loss On Drying (LOD), particle sizing, and bulk density testing of granulation.

QUALITY CONTROLQUALITY CONTROL11. The Validity Assessment Report was inadequate in that :

- The auditors failed to adequately support some of their conclusive statements. For example, the drug substance ………… was

erroneously described by the auditors as having changed from unmilled to milled : the process validation was evaluated as satisfactory without noticing that the protocol was approved after the validation lots were completed.


13. The current protocol for validating the manufacturing for ……… does not state the process parameters that would be covered by the validation. For example, it does not require a comparison between bio - availability batches and validation batches.

14. The firm lacks SOPs which specify the manner in which production blend samples are to be withdrawn (by technical services or Quality Assurance) and subsequently handled in the laboratory, such that the sampling and testing is consistent with commitments made in specific ANDA. For example,

QUALITY CONTROLQUALITY CONTROL Blend samples for ………… are received in the laboratory in individual

bottles which represent a composite of the top, middle and bottom from individual drums. The contents of these bottles are pooled in the Quality Control Laboratory, according “to practice”. The composite is analyzed, to obtain a result which is titled, “in-process Blend Sample Data”.

15. There is no assurance that the sampling method employed for cleaning

validation of equipment could detect low level of residuals. A non-quantitative method ………. transfer resulted in low recoveries of spiked sampled via HPLC. There is no minimum requirement for the percent recovered from spiked samples to assure adequate cleaning. For example,

a. During the cleaning validation of ……… capsules, 63% from spiked

samples was recovered.b. During the cleaning validation of ………… capsules, 89% from spiked

samples was recovered. 16. Process validation studies for products using the fluid bed dryer have no

specifications established for Loss On Drying (LOD), particle sizing, and bulk density testing of granulation.

QUALITY CONTROLQUALITY CONTROL17. The firm fails to meet commitment made in NDA / ANDA applications as

follows :

a. In spite of the firm’s commitment to perform in-process blend uniformity testing, only a composite of the blend is tested.b. In spite of the firm’s commitment to perform in-process blend uniformity testing from the top, middle and bottom of the left and right of the blender, the first four lots sampled after the validation lots were sampled only from the drums.c. The required in-process test for potency on the bulk syrup prior to filling was not performed on two lots. The ANDA commits to performing this test on all lots.

18. SOPs for sampling after cleaning do not specify the method that should be used , nor do sampling records specify where the sample was taken.

19. …….firm has not addressed the following :

a. Analytical methodology for determination of drug or other chemical residues .

b. Length of time which may elapse between use of equipment and the subsequent cleaning operation.

c. Cleaning solvents are not specified in the SOPs.

QUALITY CONTROLQUALITY CONTROL20. The investigation into the acquisition and release of aluminium stearate of the

wrong grade obtained from an unapproved source failed to identify that the wrong grade of material was ordered from the vendor. Further, the evaluations of other materials to identify other sourcing / grade problems was not documented and SOPs for the purchasing of raw materials did not include a requirement to reference testing standards.

21. Product performance was not evaluated with respect to the use of

alternatively sourced excipient in the production of …… tablets. Subsequent batches had marginal dissolution results which were attributed to the use of this raw material.

22. Preservative effectiveness testing is not performed as part of the stability

program. In addition, the finished product release specifications are inadequate, in that, there is no quantitative testing performed for determination of…… levels.

23. …..SOP ….permits out of specification data to be averaged with data within

specification for product release. There are no procedures in the SOP that address rejecting or recalling a lot when out of specification results cannot be validated.

QUALITY CONTROLQUALITY CONTROL24. Some laboratory equipment is being used with control settings or under

adverse environmental conditions and / or ranges not established during validation. For example :

- The dissolution testing machine was observed to be sitting on a bench top that was vibrating. The dissolution test apparatus could be felt to be vibrating when a hand was placed on the dissolution tank surface. The vibration was being caused by two continuously operating bench top

stability chambers located on the same lab bench. 25. The HPLC methodology for the determination of ……………… is inadequate

because this method establishes the use of a working standard preparation of double the expected sample concentration.

26. Batch ………….. did not meet the assay specifications during the stability

studies at …………. months. This lot has ……… months of expiration period. The assay failure was using the official methodology, however, this failure was disregarded because passing results was obtained in a retest using non - approved methodology. In addition, this lot has registered OOS results at the ………… month intervals. No action has been taken with this lot which does not meet product specifications and is still within the expiration period.

QUALITY CONTROLQUALITY CONTROL27. No documentation was provided regarding the stability incubator which

reportedly failed during stability studies of ………… No documentation was available for the installation and calibration of this incubator nor was a record available documenting the cause for the equipment malfunction / failure.

28. The visual inspection of stability and retention samples for colour is subjective. To date, no standards are used in the visual examination for colour.

29. …The firm lacks the controls necessary to ensure the accuracy and reliability of analytical data generated by the laboratory. Although more than ….. of the “out of specification” laboratory investigations were attributed to (analyst error) there was no documentation that any retraining was conducted. None of the investigation reports reviewed listed retraining the analyst as the corrective action to prevent recurrence.

30. … There is no traceability to show how the …..%Match acceptance level was established for IR standard Vs test article. For example :

- There is no SOP or statement stating which IR computer library reference standard chart to use during IR testing of drug raw materials. On atleast one occasion one of the IR computer libraries matched below the … %comparability accept/reject level while a second of the libraries was above the…..%level and the raw material was passed based on the second library level.

QUALITY CONTROLQUALITY CONTROL31. System Suitability Aspects :

a. Your firm limits for chromatographic purity specifically is too permissible. Your firm allows an RSD limit for the system suitability of not more than (NMT) …………… (which is too high).

b. A theoretical value of ………… (borderline) was reported at the beginning of a chromatographic run. The theoretical value for the last injection of the run was about …………… indicating the degradation of the initial system suitability conditions.

c. The equipment did not remain suitable during the whole chromatographic run.

d. There are no studies that indicate stability for samples prepared for ………. hours prior to the analysis determination.

32. The infrared identification tests performed are questionable. The comparison

between standard and sample maxima wavelengths could not be completely performed because the wavelengths data in the standard spectrum were illegible. Specifically, we would not match the maxima of …………. standard spectrum with the complaint sample spectrum.

QUALITY CONTROLQUALITY CONTROL33. SOP …permits out of specification data to be averaged with data that is within

specification for product release. There are no procedures in he SOP that address rejecting or recalling a lot when out of specification results cannot be validated.

34. The laboratory investigation for the …………. That initially failed at ………….. months concluded that the “UV spectrophotometric determination used seems to be unsuitable for the ………. Test”. However, this test was the same that your laboratory has been using routinely during several years for the …………… determination. The problem resides within your laboratory personnel that cannot reproduce the method. There is no proper investigation done that proves that the method is inappropriate because it did not identify the potential source of error of the method, for example : traces of ………….. that stay in the …………. or the effect of the shift of maximum of absorbance, caused by changes in ………. of final sample preparation.


QUALITY CONTROLQUALITY CONTROL36. Product performance was not evaluated with respect to the use of

alternatively sourced excipient in the production of …… tablets. Subsequent batches had marginal dissolution results which were attributed to the use of this raw material.

37. Preservative effectiveness testing is not performed as part of the stability program. In addition, the finished product release specifications are inadequate, in that, there is no quantitative testing performed for determination of…… levels

38. SOP …….. “Repeat Analysis for Confirmation of Unexpected Results” :

a. Does not establish a time limit for the investigation.

b. Uses re - sampling for rejecting analytical results.

c. Utilizes an “outlier” test for invalidating / rejecting content uniformity tests (a statically based test)

d. Uses re - sampling to assume a sampling or preparation error.

QUALITY CONTROLQUALITY CONTROL39. Regarding the firm’s laboratory training :

a. Analysts are only required to read the Firm’s SOP’s and sign a document to that effect. b. Firm records show that analysts covered more than 20 SOP’s the same

day.c. Firm records show that analysts received this training once they are hired, but not thereafter.d. Training is not provided on a continuing basis and with sufficient frequency.

40. Purity Thin Layer Chromatography (TLC) testing methods have not been adequately validated. Method validation protocols do not contain quantitative acceptance criteria for studies such as specificity, detectability, reproducibility, and ruggedness. For example :

a. For drug substance purity testing of ………… in the lab ruggedness results for “known” unknown were not comparable between the methods

development laboratory and the quality control laboratory.b. Results are not reported bearing quantitation limits in mind, i.e., faint

spots seen on plates are reported as 0.0% as opposed to less than a standard spot or detection limit.

QUALITY CONTROLQUALITY CONTROLc. Acceptance criteria do not specify that all impurity spots are separated

from each other and that Rf / RRf values clearly identify one impurity from another.

41. Raw data for in - process TLC analyses such as reaction completion, purity, etc.

are non - existent or undocumented. For example, standards spotted and compared to samples are not noted in any record and documentation of TLC results (e.g. photographs do not exist). In addition, methods used for reaction completion - purity testing of …………. have not been validated according to the firm’s In - Process Laboratory Methods Validation Protocol. The protocol calls for sensitivity and linearity checks covering the expected by - product range.

42. Validation - The firm failed to follow their validation protocol in several areas.

Examples include : a. Protocol calls for 10 x 50 g (500g) samples from final blend. Actual

sample size was recorded as 550g and does not reflect individual subsamples. b. The batch record does not reflect that sample was collected for angle

of repose and density. Laboratory records reflect these analyses were performed.

QUALITY CONTROLQUALITY CONTROL43. Deficiencies involving all High Performance Liquid Chromatography (HPLC)

equipment and Computer Software System ………… include :

a. Failure to have a written program or schedule to make back - ups of product specific assay methods on all HPLC equipment.

b. There is no data available to assure that all the instrument / software systems have been certified or validated to assure proper

performance and integrity of data.c. There is no established program for securing the programmed methods or data entry in all systems to assure they are not intentionally or inadvertently altered.

44. Laboratory personnel do not record the position of samples and standards in the run until after they are loaded in the HPLC. The position of samples and standards in the HPLC is retrospectively recorded from memory.

45. Continued and repeated failure to maintain all chromatogram printouts and test reports. Chromatographic printouts (GC & HPLC) were discarded and not made part of stability and finish product analytical reports without valid scientific justification for voiding and discarding test results. There was no system in place to verify and assure test data is not discarded and voided chromatograms are adequately investigated.

QUALITY CONTROLQUALITY CONTROL46. There are no procedures or guidelines to direct analysts on how to handle

suspicious or invalid analytical results. The only written instructions was a memo from the lab supervisor dated………… on which the recording of the reason for voiding chromatograms was required. However, no guidance is given as to what situations the analysts are authorized to void test results and what steps must be taken to conduct an adequate cause identification investigation.

47. Your in-house and contract laboratories failed to consistently follow system suitability requirements of USP when conducting stability assays and data elements of the method validation. HPLC charts and analyst notebooks show standard preparation ………….. was not injected enough times to obtain replicate chromatograms to find out if results meet the ………. RSD limit.

48. There is no assurance raw material samples of active components represent each shipment of each lot.

- Identify testing is not done on raw material taken from actual containers. USP identity, microbiological and Loss on Drying (LOD) assays are conducted on “side” samples that are received in various packaged forms from the supplier. The supplier packages and mails the “side” samples separate from bulk containers.

QUALITY CONTROLQUALITY CONTROL49. No alarm system is available in the stability chambers, in order to detect and

notify the responsible person(s) of any changes occurring in the already set conditions of temperature and humidity. At the present time, the conditions are recorded, and visually observed, and any change is detected only if you visually inspect the conditions.

50. There is no knowledge, identification, or specifications established for

residual solvents or organic volatile impurities present in the active drug substance ……….. In addition, ……………. raw material has not been qualified from a microbiological perspective, total microbial limits have not been established and potentially objectionable organisms have not been identified.

51. The change from the former USP titration method to the (Firm’s) HPLC method

was not by supplement, but rather placed in an annual report. The (Firm’s) method was listed as an “alternate” method but it is the only method currently approved.

52. The microbial purity test procedures conducted on finished product, raw

material and in - line samples are not validated in that preparatory testing has not been conducted utilizing the media manufactured by an outside facility. Additionally, the procedures are inadequate in that :

QUALITY CONTROLQUALITY CONTROLa. There is no growth promotion testing conducted on the media to demonstrate that the media can support microbial growth.b. There has been no testing conducted to support the shelf life of media that is prepared in - house and stored for an undocumented amount of time.

c. The use of peptone water is not described as a diluent in the procedure nor has its use been documented during validation procedures.

d. There is no documentation to support the use of the pour plate method rather than the multiple - tube method as described in the USP for

products tested.

53. The samples for microbial testing are prepared and examined on second shift where :

a.There are no formal training procedures for employees working the in microbiology lab.b. There has been no documented training of the employee who independently works on the second shift.c. There is no system for the evaluation of employee(s) working on the

second shift.

54. For validation of the analytical method for ………….. the firm did not perform a forced degradation study for the placebo.

QUALITY CONTROLQUALITY CONTROL55. The usual laboratory practice was to retest only test lots with out-of-

specification test results and not to retest lots with “passing” test results. In most cases, the “passing” lots were not retested even when there was a substantial discrepancy between the original and retest results for the retested lots.

56. There is no statistical basis or scientific rationale for the sampling plan used

to perform the physical examination (color / clarity) of stability samples. Current written procedures do not describe sample size or acceptance criteria for this test. In addition, the test for colour is subjective. No standards are used to aid in the visual examination for color.

57. The Quality Unit has not consistently been responsible for the approval or

rejection of specifications and procedures in place in that the unit has been bypassed.

a. Unwritten laboratory procedures, which had not received quality unit

approval, were used to invalidate out-of-specification disintegration results for ……………….. In laboratory investigation reports, analyst error was inappropriately assigned.

QUALITY CONTROLQUALITY CONTROL b. Lot ………… failed to meet assay specifications at the 24 month / 30

°C stability testing interval (expiration). Records show that at 18 months this lot already showed a downward trend in assay, however, no further action or monitoring was undertaken to insure this lot’s potency through its

expiration date. c. Hold times for ……………. were changed in the system via a memo

from the Pharmaceutical Technology group, bypassing the Quality unit decision making responsibilities regarding specifications that affect drug quality.d. The decision to recall ………… lot ……………, that had failed at a contract laboratory was delayed more than two months until retest as well as

resample results were evaluated.

58. Complete independent analyses are usually not performed for the “retest” samples. Retest aliquots of injection products are usually all taken from the same new vial or syringe or the same fresh pooled composite. For tests with HPLC chromatographic methods, all of the samples are analyzed in the same chromatographic run versus the same fresh standard solutions.

59. At least seven Laboratory Investigation Reports reviewed during the inspection indicate the corrective action plan to instruct analysts to follow procedures more carefully, all analysts involved had been certified to conduct the analyses where analyst error was found to be the most probable cause for the OOS results.

QUALITY CONTROLQUALITY CONTROL60. Linearity, accuracy and selectivity degradation studies were done for assay

method validation. The chromatograms show tailing effect, but a tailing factor calculation is not included in the firm’s method validation protocol.

61. Failure to assure that the required humidity and temperature of the Stability

Samples Storage Room is adequately distributed throughout the room. 62. The procedure for rejection of analytical data and reassay of samples is

inadequate, in that there is no information explaining in detail how the retesting is conducted. There is also no information explaining at what point testing should end and the product be evaluated.

63. FT - IR calibration procedures are inadequate to insure that the instrument is

properly operating and capable of generating accurate data. The firm’s wave number specification between …………. and ………… is …………… cm. The National Institute of Standards specifications for this region is 2 cm. There is no historical data to justify the firm’s procedure of calibrating analytical instrumentation once or twice a year. The frequency of instrument calibration and maintenance, and the procedures used to calibrate some instruments are

insufficient to insure that the equipment is functioning properly. For example : HPLC detectors, pumps and injectors.

QUALITY CONTROLQUALITY CONTROL64. Complaint ………… of yellowish colour in …………, was investigated using only

Method ………. which uses a GC. Small broad peaks are noted in the chromatograms of the complaint and retention samples. However, no corroboration of those peaks was conducted nor other techniques were used to determine the yellow contaminant in the complaint sample. No other packaging presentations that used the same bulk or batch production records, packaging records and laboratory records were investigated. Not all the retain samples were inspected. Your firm’s investigation was closed stating that no strange peak was observed in the chromatograms.

65. There is no system for tracking out-of-specification microbiological test results. For example, the firm uses ……….. biochemical test kits for identification of gram negative bacteria. The test results are recorded on cards, however, there is no system for tracking this data to assure that all positive test results are followed up and that investigations are conducted in a timely manner.

66. Laboratory notebooks for the Related Substances testing for stability trials of ………….. validation batches failed to accurately reflect the testing conditions and results. For example :

a. Retention factor values for all spots for each injection were not recorded.

QUALITY CONTROLQUALITY CONTROLb. In cases in which multiple samples were injected on the same plate there was no indication as to which injection was used to establish the standard gradient.

67. The finished dosage form of …………. was out of specification for individual

and total impurities. There is inadequate documentation to justify invalidating the original and two retest out of specification related substance results and accepting the one within specification test. Evaluation of the first set of chromatograms did not show excessive baseline noise, and there is no documentation of contamination as suggested in the retest analysis. The test values obtained on a new HPLC column with freshly prepared mobile phase indicate the product exceed specifications for individual and total impurities.

68. HPLC mobile phase buffers are stored at room temperature in large quantities

and used for at least one month. There are no SOPs for preparing and using the mobile phases for one month or more, nor are there procedures to check the pH of buffers prior to using. Stability studies were not conducted to insure that the buffers were adequate for use after storage. Analytical data acquired for several products that were analyzed using the buffers after storage indicates some may be unstable and incapable of producing accurate and reliable results.

QUALITY CONTROLQUALITY CONTROL69. Analytical notebook and chromatographic data from the contract laboratory

was not thoroughly reviewed by responsible individuals in the firm for accuracy, completeness, and compliance with USP and cGMP specifications. The notebook data lacks the date analytical work was initiated, reference standard purity, and the factors and calculations used for quantitation.

70. Quality Control chemistry and stability laboratory investigations are inadequate. The investigation report does not include the corrective actions necessary to prevent similar recurrences. The reports do not indicate if similar out of specification results were reviewed, and if other lots are affected.

71. ……capsules were packaged using a new cap inner seal which had to be heat activated and no lots were placed on stability. These products were given 5 year expiration dates.

72. …….Firm has not performed validation studies to determine if the use of metal caps provides adequate protection against foreseeable external factors during storage of the …products.

73. …..there was lack of a standard operating procedure to test, examine and release metal caps. Lots of metal caps received before this date were released using an SOP for plastic caps.

QUALITY CONTROLQUALITY CONTROL74. ……metal caps and liners used by firm may not be equivalent to plastic caps

previously used on the tablets & capsules. For example:

a. No statement of equivalency was received from metal cap Supplier / manufacturers that the metal caps used by firm in place of the HDPE

caps were plastic caps as required in firm's protocol……

b. The Specification Document reveals that specifications for the metal caps backing liner are not the same as plastic caps.

75. …….Rayon USP was specified as a filler in bottles of …… tablets and capsules .According to the specification sheet , (from manufacturer), the type of rayon supplied did not meet USP specifications for absorbency nor titanium dioxide content.

76. There is no established limit for unknown HPLC peaks found during cleaning effectiveness studies. In addition, no attempt has been made to identify these unknown HPLC peaks.

QUALITY CONTROLQUALITY CONTROL77. (Firm) is not following its Stability Testing Program SOP ……….. which requires

the smallest and the largest package size from each of the first three batches be placed on both accelerated and room temperature stability studies when packaging changes, formulation changes and / or change(s) in the manufacturing process occur. For example :

a. No lots were placed on stability when a manufacturing change

occurred and a heat tunnel was placed into use to aid in sealing …………… plastic cap inner seals that had repeatedly failed the normal sealing process.

b. Two lots of 50 mg capsules in 50 count bottles ; three lots of 100 mg

tablets in 500 count bottles and 6 lots of 100 mg capsules in 50 count bottles all with the packaging change from plastic to metal caps were manufactured and only one lot of each type was placed on accelerated stability.

c. Approximately ………….. lots have been manufactured with the

packaging change of substituting rayon for cotton as a filler. Only one lot of each strength and bottle count was placed on accelerated temperature stability.

QUALITY CONTROLQUALITY CONTROL

78. Products with metal closures were released for distribution bearing 5 year expiration dates before the 3 month accelerated stability studies had been completed on the single lot placed on accelerated stability for each product configuration and no room temperature data had been generated.

MICROBIOLOGYMICROBIOLOGY 1. The microbial purity test procedures conducted on finished product, raw

material and in-line samples are not validated in that preparatory testing has not been conducted utilizing the media manufactured by an outside facility. Additionally the procedures are inadequate in that :

a. There is no growth promotion testing conducted on the media to demonstrate that the media can support microbial growth.

b. There has been no testing conducted to support the shelf life of media to demonstrate that the media that is prepared in-house and stored for an undocumented amount of time.

c. The use of peptone water is not described as a diluent in the procedure nor has its use been documented during validation procedures.

d. There is a documentation to support the use of pour plate method rather than the multiple tube method as described in the USP for products tested.

MICROBIOLOGYMICROBIOLOGY 2. …. The samples for microbial testing ate prepared and examined on 2nd shift

where :

a. There are no formal training procedures for employees working in the microbiology lab.

b. There has been no documented training of the employee who independently works on the 2nd shift.

c. There is no system for the evaluation of employee (s) working in the 2nd shift.

3. Failure to assure micro-organism reduction of atleast 10-6 in the bio-burden challenge for the terminal sterilization process during validation when the verification of the inoculating source showed only to contain micro-organism at 10-4.

4. The firm lacks validation of temperature at which plates are incubated for total viable count for bacterial content of purified water. Incubation temperature is…degrees C for a period of….. hours. No comparison is made between the firm’s temperature and time of incubation and a lower temperature and longer time of incubation to determine if the firm’s method is capable of maximizing detection of bacteria.

MICROBIOLOGYMICROBIOLOGY 5. Failure to validate the (process) with maximum load during bio-burden study

to assure sterility with the sterilizer at this load. Although you demonstrated proper levels of heat are achieved with your heat penetration / heat distribution study this does not measure the microbial resistance with the product.

6. ….The …..filter sterilization validation data for ……injection shows that the validation did not simulate “worst case” production conditions regarding the size of microrganisms in the drug product. The validation report number.... reported that the control filter (..micron) retained the challenge organism was not small enough to challenge the sterlizing filter’s (…micron)porosity.

7. …….use-point water samples from the compounding tank and accessories wash rooms are not representative of the water used for cleaning. Tubing is attached to the water drop for cleaning, whereas a sterile hose is used to collect samples for microbial analysis and bio-burden testing.

MICROBIOLOGYMICROBIOLOGY 8. …..Quality control unit does not maintain complete written record of

investigations, root causes and conclusions following unexpected processing discrepancies or failures. For example :

a. Complete investigations were not conducted when non-sterile bulk exceeds microbial limits of … CFU/ml.

b. Sterility media fills are conducted to monitor the aseptic fill process. The firm’s procedure allows a …..% sterility failure rate , without investigation to determine root cause. Examples of events that were not investigated include:……

9. The …………. filter sterilization validation data for ………… Injection shows that the validation did not simulate “worst case” production conditions regarding the size of micro - organisms in the drug product. The Validation Report Number ………. Reported that the control filter (………….. micron) retained the challenge organism suggesting that the organism was not small enough to challenge the sterilizing filter’s (……… micron) porosity.

MICROBIOLOGYMICROBIOLOGY10. Use - point water samples from the compounding tank and accessories wash

rooms are not representative of the water used for cleaning. Tubing is attached to the water drop for cleaning, whereas a sterile hose is used to collect samples for microbial analysis and bioburden testing.

11. The firm’s practice of spraying the sterile fill area with ……….. after a failing environmental result has not been validated to show that it controls microbial growth and that it does not leave a residue which would contaminate the product being produced.


MICROBIOLOGYMICROBIOLOGY13. The firm’s Airborne and Surface Bioburden Monitoring of the production area

is deficient in that : a. The firm lacked a documented schedule and frequency for the

monitoring and testing of the controlled environment. b. The firm failed to identify the location and specific areas in which

microbial sampling is performed, e.g. the ………….. room (location) and next to the …………… (specific area).

c. The firm’s corrective action for bioburden testing is inadequate, for

example :

1. There is no adequate documentation of the firm’s corrective action when microbial limits are exceeded.

2. The firm failed to adequately identify the micro-organism isolated during microbial testing for future reference.

14. The sampling protocol for fluid bed dryer microbiological evaluation did not

include sampling of the fluid addition nozzle or the compressed air pathway.

MICROBIOLOGYMICROBIOLOGY15. The firm has not established microbial content specifications for all drug

substances used in the manufacture of their sterile small volume parenteral products. Where specifications exist the firm is not rejecting raw material lots found to contain potentially hazardous organisms. For example :

a. There has been no qualification of the microbial content of the active

drug substances used to manufacture the sterile injectable drug product. There are no microbial specifications for the active drug substances.

b. The following lots of raw material were tested for microbial content, found to contain potentially hazardous microbial organisms but were released for use in production, based on data such as back challenge testing.

16. The “Identification of Bacteria” flowchart depicts that the catalase test is to be

the first test performed if gram positive cocci (GPC) bacteria are being identified. Also, it shows that the oxidation / fermentation test is to be performed if the MSA test is negative. However, the catalase and oxidation / fermentatio tests were not performed in the testing of MSA (-) GPC micro-organisms in at least 17 lots of product.

MICROBIOLOGYMICROBIOLOGY17. Failure to take remedial action or investigate the presence of mold,

Aspergillus versicolor and Aspergillus niger, found in the pure steam generator water sampled dated ……………. The water for the steam generator is supplied by the WFI system. The steam supply goes directly into the ………….. sterilizer where it comes into direct contact with clean room equipment and product container components, i.e., rubber stoppers for vials. There is no evaluation of the effect the molds may have had on the steam supply and rubber components.

18. Investigations into WFI contamination, which were found to be incomplete.

For example, there is no data to support the conclusion of the investigation, which states that the “most likely source of the micro-organisms is the saline rinse”. There was no testing of saline solutions used on this test date.

19. The firm lacks validation of temperature at which plates are incubated for total

viable count for bacteria content of purified water. Incubation temperature is …………… degrees C for a period of ………… hours. No comparison is made between the firm’s temperature and time of incubation and a lower temperature and longer time of incubation to determine if the firm’s method is capable of maximizing detection of bacteria.

MICROBIOLOGYMICROBIOLOGY20. The sampling / monitoring of factory ……… endotoxin reduced water was

inadequate in that samples are not taken from the flexible hose at the points of use. The flexible hose is used to charge water during the manufacture of APIs.

21. The flow of raw materials, in - process granulation, and bulk tablets was

inadequate to prevent microbial contamination of ……….. tablet lots. For example, one conclusion drawn by the microbiology laboratory regarding contamination was that the loading dock, which gives access to the oven drying room, is a main port of entry for mold spores into the building. Further, the firm does not perform routine microbiological monitoring of the facility.

22. Preparatory testing for the microbiology methods used for bioburden

detection during cleaning validation (swabs and rinse samples) did not include an evaluation of ………… which is the test method used during these cleaning (bioburden) studies.

23. ………environmental monitoring of aseptic filling operations does not occur

during dynamic conditions.

MICROBIOLOGYMICROBIOLOGY24. ……The system in place which provides for supervisory review of sterility test

media sterilization cycles, does not assure that actual cycles are reviewed for compliance with required cycles foe various media in various containers. Ex, a batch of TSB was incorrectly autoclaved for 25 minutes instead of the required 30 minutes, and the error was not detected through the normal review process but was found during an investigation into an initial sterility test failure.

25. Media Fills :

a. The last media fills on line ………… are inconclusive because they were filled in amber ampules which is inappropriate for detecting turbidity

(contamination).b. Media fills have not simulated product fill times. Media fills have lasted … hours, product fills run .. to .. hours. (cumulative stoppage time associated with fill weight checks during routine production; manual stoppering is done only when needed during media fill and for the maximum no. of times that occur during routine production)c. Media fills do not validate the allowed hold-time of bulk from compounding to filling, nor is there bioburden data to support this hold time.

MICROBIOLOGYMICROBIOLOGY26. Investigation into the positive media fill of ……… was incomplete in that it did

not identify from what portion of the fill the positive vials were collected nor evaluate people, room, or other product.

27. A review of reverse osmosis water system documents showed the frequency

for sanitizing system and what events would necessiate sanitizing system had not been identified. The procedure for “Evaluating bacterial growth in deionized water system” does not identify the microbial testing system…..beyond calling it purchased bacterial samples.

28. Sterile filter validation for…… did not include an evaluation of bioburden

inherent to this ophthalmic solution nor an evaluation of the effects of the product on the bioburden (i.e. size of organisms)

29. Process validations performed on all products included Bioburden History

Data to evaluate the longest number of days each solution was held in temporary storage with acceptable bioburden values. However, the historical storage times were not considered when establishing the maximum recommended days to store.

MICROBIOLOGYMICROBIOLOGY30. SOP, ‘Environmental Monitoring Program’ specifies warning and action limits

for sampling plates used to monitor the bioburden on the floors,walls and machinery surfaces in the manufacturing areas. Validation studies have not been performed to establish action and warning limits.

31. ……The purified water system used in the manufacturing of Rx, OTC and

nutritional products has not been validated . for example:

a) The firm uses the compendial microbial limit test for total plate count , total yeast and mold and Pseudomonas. The USP states that the compendial microbial limit tests is not designed for the testing of ingredient waters.b) Chlorine, a common additive to municipal water systems, is not inactivated by the firm or the contract laboratory with a dechlorinating agent (i.e. sodium thiosulphate) prior to testing. Results generated by the contract laboratory are not a true representation of actual microbial levels within the city water.

32. …….Review of the endotoxin reduction validation studies for ……products

revealed no control was conducted to determine the amount of endotoxins that can be recoverd from receivers after seeding the tank with pyrogens.


33. The firm’s current environmental monitoring report is inadequate. The report does not trend the amounts or types of organisms found at each test location, but reports monthly averages of organisms detected. The data is not trended on a monthly basis but is reported annually.

34. ….. On ……, the filling of ……… was affected by a plant-wide power failure. Bioburden monitoring was not performed until the next day

35. ….. Failure to validate the LAL gel clot test method for endotoxins in that inhibition and enhancement has not been done on drug substance raw material to demonstrate that the substance does not of itself inhibit or enhance the reaction or otherwise interfere with the test.

MICROBIOLOGYMICROBIOLOGYA. Microbial Limit TestMicrobial Limit Test : :

1. There is a documentation to support the use of pour plate method rather than the multiple tube method as described in the USP for products tested.

2. …..Quality control unit does not maintain complete written record of investigations, root causes and conclusions following unexpected processing discrepancies or failures. For example :

a. Complete investigations were not conducted when non-sterile bulk exceeds microbial limits of … CFU/ml.


MICROBIOLOGYMICROBIOLOGY 4. The firm’s corrective action for bioburden testing is inadequate, for example :

a. There is no adequate documentation of the firm’s corrective action when microbial limits are exceeded.

b. The firm failed to adequately identify the micro-organism isolated during microbial testing for future reference.

5. The firm has not established microbial content specifications for all drug

substances used in the manufacture of their sterile small volume parenteral products. Where specifications exist the firm is not rejecting raw material lots found to contain potentially hazardous organisms. For example :

a. There has been no qualification of the microbial content of the active

drug substances used to manufacture the sterile injectable drug product. There are no microbial specifications for the active drug substances.

b. The following lots of raw material were tested for microbial content, found to contain potentially hazardous microbial organisms but were released for use in production, based on data such as back challenge testing.

MICROBIOLOGYMICROBIOLOGY 6. The “Identification of Bacteria” flowchart depicts that the catalase test is to be

the first test performed if gram positive cocci (GPC) bacteria are being identified. Also, it shows that the oxidation / fermentation test is to be performed if the MSA test is negative. However, the catalase and oxidation / fermentatio tests were not performed in the testing of MSA (-) GPC micro-organisms in at least 17 lots of product.

7. ……The purified water system used in the manufacturing of Rx, OTC and nutritional products has not been validated . for example:

a. The firm uses the compendial microbial limit test for total plate count , total yeast and mold and Pseudomonas. The USP states that the compendial microbial limit tests is not designed for the testing of ingredient waters.

b. Chlorine, a common additive to municipal water systems, is not inactivated by the firm or the contract laboratory with a dechlorinating agent (i.e. sodium thiosulphate) prior to testing. Results generated by the contract laboratory are not a true representation of actual microbial levels within the city water.

MICROBIOLOGYMICROBIOLOGY 8. Process validations performed on all products included Bioburden History

Data to evaluate the longest number of days each solution was held in temporary storage with acceptable bioburden values. However, the historical storage times were not considered when establishing the maximum recommended days to store.

B.B. WaterWater:

1. …….Use-point water samples from the compounding tank and accessories wash rooms are not representative of the water used for cleaning. Tubing is attached to the water drop for cleaning, whereas a sterile hose is used to collect samples for microbial analysis and bio-burden testing.

2. A review of reverse osmosis water system documents showed the frequency for sanitizing system and what events would necessiate sanitizing system had not been identified. The procedure for “Evaluating bacterial growth in deionized water system” does not identify the microbial testing system…..beyond calling it purchased bacterial samples.

MICROBIOLOGYMICROBIOLOGY 3. Sterile filter validation for…… did not include an evaluation of bioburden

inherent to this ophthalmic solution nor an evaluation of the effects of the product on the bioburden (i.e. size of organisms)

C.C. AirAir ::

1. The firm’s practice of spraying the sterile fill area with ……….. after a failing environmental result has not been validated to show that it controls microbial growth and that it does not leave a residue which would contaminate the product being produced.

2. The firm’s Airborne and Surface Bioburden Monitoring of the production area is deficient in that :

- The firm lacked a documented schedule and frequency for the monitoring and testing of the controlled environment.

3. The flow of raw materials, in - process granulation, and bulk tablets was inadequate to prevent microbial contamination of ……….. tablet lots. For example, one conclusion drawn by the microbiology laboratory regarding contamination was that the loading dock, which gives access to the oven drying

room, is a main port of entry for mold spores into the building. Further, the firm does not perform routine microbiological monitoring of the facility.


4. Preparatory testing for the microbiology methods used for bioburden detection during cleaning validation (swabs and rinse samples) did not include an evaluation of ………… which is the test method used during these cleaning (bioburden) studies.

5. ………environmental monitoring of aseptic filling operations does not occur during dynamic conditions.

6. SOP, ‘Environmental Monitoring Program’ specifies warning and action limits for sampling plates used to monitor the bioburden on the floors,walls and machinery surfaces in the manufacturing areas. Validation studies have not been performed to establish action and warning limits.

7. The firm’s current environmental monitoring report is inadequate. The report does not trend the amounts or types of organisms found at each test location, but reports monthly averages of organisms detected. The data is not trended on a monthly basis but is reported annually.

MICROBIOLOGYMICROBIOLOGYD.D. EnvironmentEnvironment : :

1. The sampling protocol for fluid bed dryer microbiological evaluation did not include sampling of the fluid addition nozzle or the compressed air pathway.

E.E. SterileSterile : :

1. Failure to validate the (process) with maximum load during bio-burden study to assure sterility with the sterilizer at this load. Although you demonstrated proper levels of heat are achieved with your heat penetration / heat distribution study this does not measure the microbial resistance with the product.

2. ….The …..filter sterilization validation data for ……injection shows that the validation did not simulate “worst case” production conditions regarding the size of microrganisms in the drug product. The validation report number.... reported that the control filter (..micron) retained the challenge organism was not small enough to challenge the sterlizing filter’s (…micron)porosity.

MICROBIOLOGYMICROBIOLOGY 3. Sterility media fills are conducted to monitor the aseptic fill process. The

firm’s procedure allows a …..% sterility failure rate , without investigation to determine root cause. Examples of events that were not investigated include:……

4. Failure to take remedial action or investigate the presence of mold, Aspergillus versicolor and Aspergillus niger, found in the pure steam generator water sampled dated ……………. The water for the steam generator is supplied by the WFI system. The steam supply goes directly into the ………….. sterilizer where it comes into direct contact with clean room equipment and product container components, i.e., rubber stoppers for vials. There is no evaluation of the effect the molds may have had on the steam supply and rubber components.

5. Investigations into WFI contamination, which were found to be incomplete. For example, there is no data to support the conclusion of the investigation, which states that the “most likely source of the micro-organisms is the saline rinse”. There was no testing of saline solutions used on this test date.

MICROBIOLOGYMICROBIOLOGY6.6. Media Fills Media Fills :: a. The last media fills on line ………… are inconclusive because they

were filled in amber ampules which is inappropriate for detecting turbidity (contamination).

b. Media fills have not simulated product fill times. Media fills have lasted … hours, product fills run .. to .. hours. (cumulative stoppage time associated with fill weight checks during routine production; manual stoppering is done only when needed during media fill and for the maximum no. of times that occur during routine production)c. Media fills do not validate the allowed hold-time of bulk from compounding to filling, nor is there bioburden data to support this hold time.

7. …….Review of the endotoxin reduction validation studies for ……products

revealed no control was conducted to determine the amount of endotoxins that can be recoverd from receivers after seeding the tank with pyrogens.

8. ….. On ……, the filling of ……… was affected by a plant-wide power failure.

Bioburden monitoring was not performed until the next day


9. …..Failure to validate the LAL gel clot test method for endotoxins in that inhibition and enhancement has not been done on drug substance raw material to demonstrate that the substance does not of itself inhibit or enhance the reaction or otherwise interfere with the test.

ENGINEERINGENGINEERING 1. Procedure for documenting and tracking, repair and maintenance requests for

manufacturing equipment do not insure the appropriate prioritization or completion of requesting repair work.

2. The validation of fill room ……….. found that the velocities at the HEPA filter

face did not meet specifications in the Class 100 area. The velocities were later corrected, but air flow patterns and laminarity tests were not repeated after the filters were adjusted.

3. Air velocities within the Class 100 area of the fill rooms are not taken at work

height, that is the height at which the vials are filled and stoppered. The velocities, which are checked semi - annually, are taken six inches from the face of the HEPA filters.

4. ………….. Preventive maintenance checks performed mid-year for in-place

testing of HEPA filters in air supply units and area exhaust systems were done incorrectly in that the zero reading of the installed magnahelic gauge was not checked, and a reading was not obtained after the “zero” step to compare to the initial reading.

ENGINEERINGENGINEERING

5. The firm’s procedure : ..… entitled, “Failure Investigation Policy” is deficient in that it does not address critical system failures. For example :

a. The WFI System lost circulation and temperature [twice] for the same

reoccurring reason. On … two WFI drops reached alert levels yet there is documented “verbal” release of the system even though maintenance was still working on the system. There is no documentation of flushing of the system before its release on ……

b. 2 leaking valves were replaced ……

c. The WFI system dropped below 65 degrees for 5 hours due to

controlled air line leaks causing improper operation of a blocking valve on …………..

6. ……….. The entire water system has not been validated. For example, water from the Reverse Osmosis (RO) storage tank is stored in a Feed Tank and pumped to the still. The water is ambient and static in the feed tank, booster pump and a portion of pipe leading to the still. This static portion of the water system from the RO storage tank to the still has never been validated.

ENGINEERINGENGINEERING 7. Failure to follow Change Control Procedure for …………. Systems and


a. Several software changes were reportedly made but not properly documented. For example, several changes to status prompt messages, and changes to pan speed and spray rate deviation settings.b. The vendor version installed was designated ……….., yet after modifications resulting from installation / operation qualification no new revision number was given.


9. …There are no differential pressure specifications for the sterility test clean

rooms, gowning room and general microbiology laboratory. There are no procedures for monitoring these differential pressures.

ENGINEERINGENGINEERING10. ….the water for injection and distilled water storage and distribution systems

are continuously monitored for pressure , water level, temperature and resistivity at …locations. Each location has a set point, alert and action limit. The computer which monitors and controls the water system has not been requalified in 6 years.

11. …..no alarm system is available in the stability chambers, in order to detect

and notify the responsible person/s of any changes occurring in the already set conditions of temperature and humidity. At the present time, the conditions are recorded, and visually observed , and any change is detected only of you visually inspect the conditions.

12. The firm’s USP Purified water system has not been maintained in accordance

with the firm’s Standard Operating Procedure - Periodic Maintenance and Service of the Production Water System. For example : a. The procedure requires the semi - annual integrity testing and changing of the ………… micron sterilizing filter. There is no documentation of this maintenance and the filter is only changed annually. There is no documentation of any examination of this filter.

ENGINEERINGENGINEERINGb. The sterile vent filter is required to be integrity tested semi - annually and changed annually. There is no record of the semi - annual integrity testing of this filter. Management stated that this filter is integrity tested and

changed annually. During the annual maintenance, this filter failed integrity testing.

c. The ultraviolet sanitizers (bulbs) are to be changed annually and the

sleeves are to be cleaned semi - annually. There is no record of the semi- annual cleaning of the sleeves, nor is there any record of the microbial kill effectiveness of the ultraviolet light sanitizers.

d. There is no record of the maintenance of the heat exchanger.

e. There is no documentation of a daily review of the system to assure the

integrity of the ………… gasket - clamp joints used to connect the stainless steel piping from the water storage tank to the heat exchanger.

f. There is no record of the examination of welds, stainless steel piping, tank and housings for internal contamination and passivity during the last

annual maintenance program. There is no passivation program for the system.

ENGINEERINGENGINEERINGg. There is no record of the maintenance of the ………… micron filter at the air compressor for air used to operate the throttling valve, the divert valve and the steam supply valve. The SOP requires annual changing of this filter but there is no regular maintenance program for this filter.

13. ……Written preventative maintenance procedures not developed for the firm’s WFI systems. Leakage which moistened pipe insulation was blamed for sample contamination during a water system investigation. In addition, weekly sanitization sheets document that diaphragm……….. has been leaking since ………..

14. Purified water used to flush the system after sanitization was not heated to minimize microbial contamination.

15. There is inadequate data to demonstrate that autoclave cycles for this terminally sterilized product have been validated. Three maximum load validation studies were conducted for the purpose of determining the autoclave’s cold spots for the placement of controlling thermocouples during routine production. During validation studies, one out of three cycles (for each size) resulted in high F0 valued in areas of the autoclave which were subsequently deemed as the autoclave’s “cold spots”. Controlling thermocouples have since been placed in only one of the two areas of the autoclave found cold during the three cycles.

ENGINEERINGENGINEERING16. During heat sanitization of the USP Purified water loop there is no assurance of

temperature throughout the loop (purported to be 180 °F). The water temperature is only monitored within the storage tank and following a heat exchanger. There is no monitoring of the water temperature within the production loop prior to its return to the storage tank.

17. Preventive maintenance checks performed mid - year for in - place leak testing of HEPA terminal filters and in - place leak testing of laminar flow units were done incorrectly in that the initial (installation) static pressure drop from the checklist or the history notes file was not obtained and compared to the current static pressure drop across the HEPA filter.

18. Failure to maintain a change history and have an accurate current description and / or schematic for all components of the water system. Water for Injection and Pretreatment. For example :

a. There is no history of the development of the pretreatment system prior to ………….b. The change history does not include the …………. still.c. There is no current equipment list for all major components of the system.d. The water system drawing dated …………… incorrectly shows a sample site in the WFI loop at clean room line number …………… and a sample

port at the portable tank connection.

ENGINEERINGENGINEERINGe. There is no documentation of the location of the city water points of use in the facility.f. Current drawings do not specifically identify components of the system equipment currently in use.

19. Written procedures which describe the monitoring of pressure differentials are

not complete. The procedures do not describe the instruments used and do not include instructions for the calculations needed to determine the differentials between adjacent rooms. In addition, the calculations are not recorded and the daily readings are not reviewed by anyone other than the person recording the readings.

20. The firm does not maintain a written description or an accurate pictorial

description of the Water for Injection manufacturing system. SOP ……………, entitled, “Water for Injection, Production, Maintenance and Testing” serves as the description and schematic of the system. There is no narrative describing the system, and the schematic lacks a true representation of the piping configuration, drainage ports, sampling ports, switch valves, pumps and heaters.

ENGINEERINGENGINEERING21. The pump used to deliver WFI to the vial washer and stopper washer comes

into direct contact with the water during pumping. After use the pump is disassembled and allowed to air dry. There is no documentation to show that pump head is periodically cleaned and sanitized nor is there any validation documentation to show that air drying the pump head parts does not introduce unwanted material into the washer systems.

22. The drawing of the process system was incomplete and failed to illustrate specific valves and drops in the piping between the feed tank and the spray dryer.

23. The training of employees is deficient in that employees do not always notify their supervisors about defects or problems. For example, a malfunctioning meter on a UV light located on the water system was not fixed for six weeks because the supervisor was not notified, and a second malfunctioning meter was not fixed for five weeks.

24. The entire water system has not been validated. For example, water from the Reverse Osmosis (RO) storage tank is stored in Feed Tank and pumped to the still. The water is ambient and static in the feed tank, booster pump and a portion of pipe leading to the still. This static portion of the water system from the RO storage tank to the still has never been validated.

ENGINEERINGENGINEERING25. The firm’s validation of Deionized Water System (DI) is inadequate in that the

firm has no validation specifications or frequency of replacement prior / after validation of the DI system for the filter, RO filter and UV light bulb.

26. ……There’s no sanitation schedule for the Reverse Osmosis (RO) units of the water pretreatment system. The operating manual recommends the system to be sanitized.

27. The firm’s maintenance procedure for the sterilizers is deficient in that :

a. There is no preventive maintenance procedure for the sterilizer air microbial filters used during the vacuum pressure relieve.

b. Safety pressure / vacuum mechanical gauges for both sterilizers are not calibrated nor are they used as a safety factor to ensure that computer pressure / vacuum readouts are accurate.c. The firm failed to conduct boiler chlorine and orthophosphate tests as required by the firm’s SOP ………

d. The sterilizer’s steam / water pipes retainers used to trap pipes debris during operations are not maintained. The firm has not established a

formal cleaning maintenance schedule to assure that the accumulation of debris in the retainers will not compromise the quality of the water used for the production of steam during the sterilization cycle.

ENGINEERINGENGINEERINGe. The firm did not conduct quality steam studies to assure that clean steam will be used during sterilization. f. The firm’s sterilization cycle used during the months of ………… is

inadequate in that conductivity and potassium upper and bottom parameters were not met.

28. A change in the location of the electronic ………. washer counters was made as a corrective action. However, there is no documentation demonstrating the validation of these relocated counters used for the syringe accountability. In addition, the SOP for critical system change requests (CSCR) was not followed, in that a CSCR was not issued and reviewed.

29. Air Velocity is not determined at critical filling sites with a frequency that assures the maintenance of a 90 feet / minute 20% speed during the filling operation. An outside contractor performs air velocity measurements semi - annually at filter faces. The firm performs these measurements at critical sites when media fills are conducted, which may be semi - annually. There is no routine air velocity monitoring program.

30. Technical Procedure ………….., entitled : “Protocol for the Deionized Water System Use, Monitor, and Maintenance” is deficient because it does not include the checking of the DI water system’s four pressure gauges located on the inlet / outlet lines.

ENGINEERINGENGINEERING31. The parameters used for validation lots, ……………. used to validate …….…..

Machine does not match the parameters specified in the validation protocol.

32. There is no reference in the equipment Use and Maintenance Log for tableting machine ………… concerning the problem of finding “metal particles” and “brass fragments” in the tablets from lot …………. which was tableted using this piece of equipment. This batch was ultimately destroyed for “metal contamination” of tablets.

33. There is no evidence that the following processes have been validated :

a. Plant cleaning procedures (Plant - wide including vessel and water system)

b. Process water system

c. Process steam system

d. Air system

e. Process water in - line conductivity meter and ultraviolet treatment system, including the respective automatic monitoring, alarm, and shut - down capabilities.

ENGINEERINGENGINEERING34. There is no evidence that the following equipment has been qualified :

a. Process water in - line conductivity meter.

b. Process water ultraviolet treatment system.

c. Air filters / air handling system.

35. You do not have a formal procedure for the calibration of your ……………. electronic label counter with …………. Bar code reader.

36. .…there was no formalized installation/operational qualification of the air handling /dust collection system installed……

37. ….failure to accurately record all down time resulting from process alarms and system breakdown. The only means of documenting the corrective actions to processing problems is a downtime log, but this log is not being filled out consistently and is not formally audited and verified by the quality assurance unit.

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