Monday, August 30, 2010

Sterile Production According To The New EU GMP

Regulations governing the manufacture of sterile pharmaceuticals in the US and Europe have been significantly revised over the past few years. The first milestone was set by the FDA's Guidance for Industry Sterile Drug Products Produced by Aseptic Processing" — "Aseptic Guide in 2004. In 2008, four parts of the EU GMP Guide Annex 1 Manufacture of Sterile Medicinal Products were extensively revised. Annex 1 became fully effective on 3 January 2010.

Another important document that often receives little attention is the PIC/S (Pharmaceutical Inspection Cooperation Scheme; recommendation PI 0075 "Validation of Aseptic Processes". Primarily aimed at pharmaceutical inspectors, this document also aids the pharmaceutical user in the interpretation and implementation of the new Annex 1 standards. In the course of the Annex 1 revision, the PIC/S document underwent several revisions and now corresponds with the current guideline.

The revised version of EU GMP Guide Annex 1 Manufacture of Sterile Medicinal Products

The revised version of Annex 1 primarily applies to four partial aspects:

* Clean room and clean air device classification
* Process simulation / media fill
* Bioburden monitoring
* Finishing of sterile products

Clean room and clean air device classification has been developed to be harmonised with the standard EN ISO 14644. For Process simulation / media fill the requirements were harmonised with the standards of the FDA Aseptic Guide. These standards were also adopted in the PIC/S document PI 007-5. The specifications for Finishing of sterile products generated a much higher need for text interpretation. The new specifications, particularly for capping vials, have also caused uncertainty for inspectors in the pharmaceutical industry.

To eliminate this uncertainty, the PIC/S published another document in January 2010, introducing the changes in Annex 1 and interpreting the new specifications. The document PIC/S recommendation PI 0322 GMP Annex 1 revision 2008, interpretation of most important changes for the manufacture of sterile medicinal products was prepared under the leadership of Swiss inspectors from Swissmedic.

The most controversial changes made to Annex 1 were found in the section for Finishing of sterile products and related to the capping of vials. Some statements in Annex 1 concerning this matter were clarified in the PIC/S document and are presented here in more detail. The PIC/S interpretations are supplemented with two case studies from pharmaceutical companies.

The author says...

1. "Grade A air supply" — definition, qualification and monitoring requirements (Annex 1 Section 120)

"Grade A air supply" was listed again in Annex 1 but not defined. PIC/S clearly explains the need to discern between Grade A air supply and Grade A area and defines the terms as follows:

"Grade A air supply is specifically used to describe a supply of air which is HEPA filtered, and at the point of supply meets, when tested, the non-viable particulate requirements of a Grade A area."

It is important to differentiate between the terms Grade A air supply and Grade A area. According to PIC/S, a Grade A air supply should be qualified and monitored; the qualification is to be performed in an "at rest" state. For the capping machine the "at rest" state is achieved when the air intake is switched on, the machine is operating (but without vials being fed and needing to be capped), and there is no user operation. For the transport tunnel the "at-rest" state is reached when the air intake and the conveyer are switched on and there is no user operation.

The requirements for nonliving particles are to meet Grade A area requirements. The sample is to be taken from beneath the air outlet and smoke studies are to be performed. A unidirectional air flow is not required. However, an efficient protection for the vial is to be proven, particularly an absence of ambient air entering. Rational air speed limitations should exist. Companies must determine monitoring requirements for nonliving particles and microbiological contaminations in line with a risk analysis.

2. Handling missing or displaced stoppers (Annex 1 Section 121)

Great importance is placed on the detection of missing or displaced stoppers prior to capping. These vials are to be rejected prior to capping. For validated processes the ejection of "bad vials" is also accepted after capping; but the ejection prior to capping is clearly preferred. The better the controls for correctly set stoppers and demonstrating the packaging integrity, the lower the requirements can be for the surrounding area. In the absence of such a control system, capping must be performed as an aseptic process.

3. The use of RABS or Isolators (Annex 1 Section 122)

There is no direct requirement for using RABS or isolators during capping. Human interaction in this process can also be reduced with other methods.

Company case studies

Case study 1

It is important to understand at which point vials with stoppers can be considered as sealed and how the requirements for a "Grade A air supply" should be interpreted. The selected approach for interpreting and implementing Annex 1 requirements is presented below using a case study from a pharmaceutical company:

Section 120 of Annex 1 states that: "Vial capping can be undertaken... as a clean process outside the aseptic core. Where this latter approach is adopted... and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped."

The "Grade A air supply", as defined in Annex 1, definitely does not correspond with the requirements of a clean room Grade A as defined by the EU GMP Guide; for example, where Grade B is a background for Grade A. Based on the interpretations of PIC/S, the "Grade A air supply" is the air quality at the air outlet location and this must meet the particulate requirements of Grade A.

Section 121 of Annex 1 states that: "Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials to minimise microbial contamination."

In this particular case study, a camera system, which detects displaced stoppers prior to capping, was introduced to meet this requirement. Because of the spatial configuration and the past robustness of the process these vials were not automatically discharged prior to capping. In the event that a displaced stopper is detected the machine is stopped and the employee intervenes on the vial using tweezers. The microbiological monitoring data collected so far showed no abnormalities with this method. In addition, settle plates are routinely laid out and evaluated.

Section 122 of Annex 1 states that: "Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation."

These requirements were interpreted in a way that a RABS (restricted access barrier system with gloves) is not mandatory. The equipment is cabinised, thus limiting interference, but gloves are not used. Access by employees is rather organisationally and technologically kept to a minimum, and is controlled microbiologically by the settle plates.

Case study 2

The following case study also describes the implementation of Annex 1 requirements at a pharmaceutical company prior to the publication of PIC/S document PI 0322. In this case, in addition to the European requirements, the respective American standards had to be met, as is typical for international companies.

Part IV Buildings and Design, section E "Design" of the FDA Aseptic Guide from September 2004 states: "If stoppered vials exit an aseptic processing zone or room prior to capping, appropriate assurances should be in place to safeguard the product, such as local protection, until completion of the crimping step. Use of devices for on-line detection of improperly seated stoppers can provide additional assurance."

The process described in this case study consists of:

* Filling — placing stopper — lyophilisation — stoppering inside of the freeze dryer in clean room Grade A.
* Capping under HEPA filtered air in clean room Grade C.

According to the Annex 1, the key point is to safeguard the product prior capping. Therefore the standard process capping with laminar flow in clean room Grade C was reassessed.

The core concern of the concept is the need to ensure the integrity of the containers. The specification was that the packaging combinations must be microbiologically sealed even without crimping caps. On one hand, this requires developing and optimising suitable packaging combinations; on the other hand it requires adequate process know-how, and finally ensuring a suitable process control concept.

For this concept the fundamental questions are:

* How to test microbiological tightness?
* How to handle packaging deviations and how to test the worst case combination?
* Which process control tools are necessary and suitable?

To address the microbiological tightness, a stronger and easier measurable criterion, the gas tightness, was defined. Therefore, various methods were used during packaging development to define the parameters for "gas tightness" of the packaging combinations. Methods used here were frequency modulated spectroscopy (FMS) and the helium leak test, whilst the methylene blue dye ingress test was used to check the tightness of the stoppered vials. To address the worst case, packaging combinations near the upper specification limits and tighter test limits were chosen. The packaging combinations and design space based on the parameter settings (e.g., to which stopper seat height is the seal gas proof) generated in development are used to define the production process. Furthermore, as a safeguard measure, the seat of the stopper is 100% monitored with a sensor barrier and a camera system.

With this, the validity of the process — proving reproducible stoppered vial tightness — is ensured through compliance with the process parameters.


The PIC/S document 0322 eliminated some uncertainties and clarified some requirements of the revised version of EU GMP Guide Annex 1 Manufacture of Sterile Medicinal Products. In the future, inspectors will certainly use these interpretations as a guide. However, there is still enough leeway to adapt the Annex 1 requirements to the

A Risk-Management Approach to Cleaning-Assay Validation

The authors recommend a strategy for classifying similar nonstainless-steel surfaces into three groups based upon the analytical recovery that was observed in this study.

Pharmaceutical Technology
Volume 6, Issue 34, pp. 48-55

Cleaning validation and verification are based on the premise of risk management. Several regulatory and guidance documents make this clear. The International Conference on Harmonization's (ICH) guideline on risk management outlines several approaches to making and documenting risk-based decisions (1). It clearly states that risk management should be based on scientific knowledge and that personnel should evaluate the effect of potential failures on the patient. In addition, it notes that the levels of effort, formality (e.g., use of tools), and documentation of the quality risk-management process should be commensurate with the level of risk.

The US Code of Federal Regulations states that equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product (2). In accordance with 21 CFR 211.67, ICH issued recommendations on equipment maintenance and cleaning (Q7A, Sections 5.20–5.26) for compliance and safety that include similar, but more detailed requirements (3).

The US Food and Drug Administration's 1993 guidance on cleaning inspections states that for a swab method, recovery should be established from the surface (4). The guidance contains no specific requirements about how to establish these recovery estimates, or the acceptance limits. It is up to the manufacturer to document the cleaning rationale (i.e., process and acceptance limits) for maintaining the quality and purity of the drug product being manufactured.

Cleaning validation and verification

Cleaning verification consists of routine monitoring (e.g., swab analysis) of equipment-cleaning processes. Cleaning validation confirms the effectiveness and consistency of a cleaning procedure and eliminates the need for routine testing (5). For example, cleaning limits are established to determine the maximum allowance of Product A that can carry over to Product B. The calculation of these limits is well documented and includes factors that increase the margin of safety to protect the patient (6, 7). Because it is not feasible to swab every square inch of the equipment, swabbing locations are chosen based upon factors such as how difficult the area is to clean, the size of the equipment, and the areas where product buildup is likely. All product-contact surfaces must be considered during cleaning verification to demonstrate that equipment is clean, and a recovery value is expected to be established for each product-contact surface during method validation. The recovery is used to correct the submitted swab result for incomplete removal from the surface and to compare it with the acceptance limit. This last aspect of risk management (i.e., establishing the surface recovery) is the focus of this article.

Analysts have many ways to establish the swab-recovery value for a particular product-contact surface. Stainless steel is the most common material in a manufacturing environment (see Figure 1). Some companies therefore establish a recovery value for stainless steel and apply that standard to all swab submissions. Other companies attempt to establish a recovery value for each product-contact surface for every compound. From an analytical standpoint, supporting this activity becomes arduous, if not impossible to sustain. For example, equipment in a clinical-trial materials (CTM) manufacturing area is used for many compounds in the company's portfolio. New equipment might have different product-contact surfaces. Each compound in the portfolio manufactured on a new piece of equipment would require a method revalidation to add a recovery factor for the new product-contact surface. As the number of materials of construction increases, the difficulty of sustaining that approach also increases. Grouping materials of construction for analytical-method development in support of cleaning verification and validation activities is an excellent opportunity to apply a quality risk-management approach, especially when the total product-contact surface area is considered. Stainless steel accounts for approximately 95% of the surface area in a CTM manufacturing and packaging environment. Other product-contact surfaces account for only 5% of the total surface area. When polymer surfaces are considered in a CTM packaging environment, the number of minor product-contact surfaces can grow significantly. A risk-management approach allows the majority of the time and effort to be spent on activities that ensure the cleanliness of the stainless-steel area while identifying, analyzing, evaluating, and communicating the risks associated with the small fraction of remaining surfaces. This strategy does not ignore the surfaces other than stainless steel, but divides them into three recovery groups to support analytical-method validation. By choosing representative recovery surfaces for those nonstainless-steel materials, the effort proportionally addresses the risk.

Design of experiments

Several variables (i.e., roughness average, material of construction, active ingredient, and spiked amount) were evaluated in a randomized fashion to prevent systematic bias that could be introduced by going from the lowest to the highest acceptance limit, from the smoothest to the roughest surface, or from one material of construction to the next. The initial design of experiments included two active pharmaceutical ingredients (APIs), three spiked acceptance-limit levels (i.e., 0.5, 5.0, and 50 μg/swab), seven surface types, four target roughness averages (Ra <>

The authors chose two APIs for this evaluation on the basis of their solubility profiles to represent the most- and least-soluble compounds a company would likely manufacture. Compound A, the less soluble, is slightly soluble in methanol and insoluble across the pH range, but Compound B is soluble in all solvents. In addition, Eli Lilly (Indianapolis, IN) identified Compound A as one of the most difficult compounds to clean from equipment, based on its low solubility and staining properties. A control (i.e., stainless steel 316L, 0.5 μg/swab, Compound A) was run each day that data were generated.

Equipment and operating conditions

Table I: High-performance liquid chromatography (HPLC) operating conditions.
The authors used an Agilent 1100 high-performance liquid chromatography (HPLC) analyzer (Agilent, Santa Clara, CA) for all experiments. The HPLC operating conditions were validated according to ICH standards for precision, linearity, limit of detection (LOD), limit of quantitation (LOQ) and specificity (see Table I) (8). Precision was 1.85% and 3.13% for Compounds A and B, respectively, and was determined at 0.025 μg/mL (i.e., 25% of the lowest spike). The method was linear across the equivalent range of 0.5 μg/swab to 5 μg/swab (R = 0.999). The LOQ was calculated to be 0.005 μg/mL for Compound A and 0.008 μg/mL for Compound B. The LOD was calculated to be 0.001 μg/mL for Compound A and 0.0024 μg/mL for Compound B. Swabs and solvents did not result in interfering peaks. The authors performed swabbing consistently using Texwipe Alpha large swabs (ITW Texwipe, Kernersville, NC). First, 10 vertical swipes, then 10 horizontal swipes were performed for the 2 × 2-in. surfaces. For the 4 × 4-in. surfaces, 20 swipes were executed in each direction. Methanol was used as the swabbing solvent. Spike amounts were 0.5, 5, and 50 μg per surface and were extracted into 5 mL of mobile phase, which corresponded to 0.1-, 1.0-, and 10-μg/mL standard concentrations, respectively. The authors used a Quanta FEG 200F field-emission scanning electron microscope (SEM, FEI, Hillsboro, OR) to generate the surface images.

Results and discussion

In this study, a single analyst evaluated the analytical swab recovery from a representative set of surfaces found in the CTM manufacturing and packaging areas. The surfaces were manufactured specifically for this study to have a broad range of Ras. In addition to Ra, the effect of the material of construction, acceptance limit, compound, and method variability also were evaluated. Based upon these data sets, the authors used a strategy involving three groups of materials to represent all of the surfaces in CTM operations. Merck and Co. used a similar strategy to establish five recovery groups (9). The authors expanded on Merck's strategy by adding a detailed study supporting the groups and an approach for determining the appropriate placement of new surfaces into pre-established groups.

Roughness average (Ra). The Ra targets listed above were difficult to achieve. The intermediate Ra values were significantly lower than the target values given in the design of experiments section above. Both intermediate Ra values, initially targeted for 75 and 125 Ra, were measured to be approximately 40 μin. Although the machining process at each level yielded visually different surfaces, the measured Ra changed little from surface to surface. The authors decided to proceed with the surfaces and define smooth surfaces as Ra <> 100 μin. This approach allowed for an assessment of the anticipated relationship between Ra and analytical recovery.

Figure 2
The Ra had little impact on the observed analytical-swab recovery, but the recovery was expected to improve with lower Ras. Figure 2 shows roughness grouped by surfaces that had a measured Ra > 100 μin. and by surfaces that had a Ra <>

Figure 3
Material of construction. Because Ra was eliminated as a factor contributing to recovery losses, the authors performed data analysis by combining all average recovery values and assessing the effect of the material of construction. The data in Figure 3 were first separated by API, and groups were generated to represent the logical separations in recovery. Figures 3(a–c) contain the data for the 0.5-μg spikes, the 5-μg spikes, and the 50-μg spikes, respectively. The data from the 0.5- and 5-μg spikes exhibited a trend similar to that of the 50-μg spikes. The variability in the results increased as the spiked amount decreased, and the 50-μg spike results were substantially less than that of the other spike levels.

For both compounds, the Type III hard anodized aluminum exhibited the poorest recovery. The next logical break point grouped bronze and cast iron. The recovery of Compound B from bronze suggested that the material was representative of Group 1. The recovery of Compound A on bronze was lower and more variable, however, so the authors placed bronze into Group 2. For the majority of the surfaces, the recovery of Compound A was lower than that for Compound B at a given limit. In some cases, the recovery was approximately the same (i.e., of 5- and 50-μg spikes on cast iron, and of the 50-μg spike on Type III hard anodized aluminum). In addition, the predominant trend was that the average recovery of a compound increased as the spiked amount increased on a given material of construction. For example, the recovery of Compound B from stainless steel 316L was approximately 74%, 90%, and 95% at 0.5-μg, 5-μg, and 50-μg swabs, respectively.

Figure 4
Ra was originally considered a variable in the experiments previously outlined and did not affect swab recovery. To understand the surface attributes that might contribute to incomplete recovery for the different materials of construction, the authors acquired SEM images for Group 1, Group 2, and Group 3 surfaces (see Figure 4). Stainless steel is a relatively smooth surface with some striations from machining (see Figure 4a). Cast iron has a pitted surface that could provide opportunities for an API in solution to be trapped during a spiking experiment (see Figure 4b). The anodization process makes Type III hard anodized aluminum, the worst recovery surface, porous, thereby creating the greatest opportunity to lose analyte (see Figure 4c).

Note that polymers were grouped together with metals and might not be considered to be similar on first pass. The SEM image of Lexan in Figure 4d, however, illustrated that the polymer surface was smooth, albeit with some surface debris, which prevented the loss of analyte. The polymer surface was grouped with stainless steel in Group 1. The SEM images were good supporting evidence that the groupings were logical based upon surface characteristics.

Table II: Grouping of material surface of construction.
Table II is based on the data shown in Figure 3. The top surface in Table II represents the surface that was validated for recovery in each group. This recovery value represented all others within a given group. The groupings were supplied to the CTM areas, and the group number was included on the swab submission to the analytical laboratory so that the correct recovery factor was applied to each surface. In addition, the table served as a tool for engineering to determine whether newly purchased equipment contained a new product-contact surface.

Analytical methods. The model and worst-case compound evaluation did not replace any analytical-method validation activities. Analytical recovery must be established for each compound in the portfolio, but not on all surfaces. If multiple limits are to be considered, or if a range of reporting is required, the lowest limit may be evaluated, and that recovery can be applied to all acceptance limits as a conservative estimate. In the analytical method, three recovery factors were presented: Group 1, Group 2, and Group 3. Methods could be validated for any surface within a group and could be considered representative. The authors chose stainless steel 316L because it is the most prevalent, and cast iron because it is a common material on a tablet press. Type III hard anodized aluminum is the only surface in Group 3. This strategy did not ignore any uncommon surfaces. It grouped them appropriately, swabbed them, and applied a representative recovery factor.

Variability. Method variability was evaluated by performing a control sample (Compound A, 6 replicates, 0.5-μg swab, stainless steel 316L, Ra = 3.5) each day. The mean recovery of the entire experiment was 52%. These data suggested that the swabbing ability of the analyst did not change over time. The standard deviation within a day typically was less than 6. The pooled-within-run standard deviation was 3.99 over the course of the experiments. This value was used as a criterion for grouping new surfaces. The day-to-day standard deviation was 15.34.

Figure 5
Incorporating new materials of construction into the grouping strategy. Periodically, new equipment will be introduced into the CTM area that incorporates a product-contact surface made of a material of construction that is not listed in Table II. This problem is often caused by alloys of metals that have already been evaluated and by polymers of proprietary composition. Because surface recovery must be evaluated, personnel need a way to incorporate new surfaces into the groupings outlined in Table II. When a new piece of equipment is purchased, CTM-engineering employees prepare the needed documentation to evaluate the equipment with regard to the cleaning program before use. If an identified sampling location is made of a new material of construction, the engineer asks the person responsible for the cleaning program and analytical development to perform the next steps, which are shown in Figure 5.

Suppose that new equipment incorporated three new materials: a crystalline thermoplastic polyester marketed under the trade name of Ertalyte (Quadrant Engineering, Reading, PA), stainless steel 420, and stainless steel 630. Without the grouping strategy in place, method revalidation would have to occur for all compounds handled by this piece of equipment. With the strategy in place, these surfaces are placed into groups based on model-compound recovery. No method revisions are required.

The analytical recovery of Compound A was evaluated for Ertalyte, stainless steel 420, and stainless steel 630 at the 5.0-μg/in.2 level. The authors used the validated method to evaluate the recovery of the three new surfaces compared with a representative surface from Group 1 (i.e., stainless steel 316L), Group 2 (i.e., cast iron), and Group 3 (Type III hard anodized aluminum). Recovery was evaluated for both the group representative and the new surfaces on the same two days with three replicates on each day. As an alternative, six replicates may be performed on the same day as the controls because the comparison of recovery is relative.

The new surfaces are placed in one of the three groups or define a new lower group, based on how close their average is to that of the group control. The authors obtained a cutoff value of 3.0% in the following manner. Based upon the data for the control, the within-day standard deviation was calculated to be 3.99 and was used in Equation 1. A series of one-sided hypothesis tests with an error rate of α = 0.10 were performed to assess whether the new surface mean was less than a specified control-surface mean. The confidence limit half-width for the difference between the means of two surfaces was computed using the within-day standard deviation because the replicates for each surface had to be run on the same two days, with each day treated as a block. For these calculations, it was assumed that this standard deviation was known. The lower one-sided confidence limit for the difference in means was derived using the following steps:

This calculation did not indicate a difference between a control surface and the new surface under evaluation if the recovery differed by less than 3.0%. This approach was conservative because Eq. 1 categorized a new surface into Group 2 if it differed from stainless steel by more than 3.0%, which could be viewed as a strict criterion. Because the results were obtained on the same days and runs, the authors believed that this approach was reasonable. When evaluating the recovery of a new surface, this strategy helps personnel to place each material into the appropriate group. The grouping starts with a comparison of the new surface average to that of Group 1 (stainless steel 316L) and continues sequentially. If the new surface recovery (NSR) is more than 3.0% less than that of the group reference, it is compared with the reference surface in the next lower group until a group is found with which it does not differ by more than 3.0%. If no such group is found, then the new surface forms a new, lower group. The procedure is as follows:

  • If the NSR > mean stainless-steel recovery – 3.0%, the new surface belongs in Group 1.
  • If the NSR > mean cast-iron recovery – 3.0%, the new surface belongs in Group 2.
  • If the NSR > mean Type III anodized aluminum recovery – 3.0%, the new surface belongs in Group 3.
  • If the NSR <>

Table III: Swab recovery of three new materials of construction compared with controls from each representative group.
The data for the three new surfaces are outlined in Table III. Based on this approach, Ertalyte was placed into Group 1 because the difference between its recovery and that of stainless steel 316L (i.e., Group 1) was less than 3.0% (i.e., 2.48%). The recovery from stainless steel 420 and stainless steel 630 was more than 3.0% less than that from stainless steel 316L, but greater than that from cast iron. The authors placed stainless steel 420 and stainless steel 630 into Group 2.

The placement of these two grades of stainless steel into Group 2 highlighted the conservative nature of this approach because their recoveries were only 4% and 8% less than that from stainless steel 316L. The recoveries were 12% and 9% greater than that from cast iron for stainless steel 630 and 420, respectively. Table II was updated to reflect this placement. Because the grouping strategy was conservative, it prevented the underestimation of recovery factors when assay values were reported and prevented the formation of additional groups for method validation unless the recovery value for a new surface is sufficiently low to warrant such an addition.


The authors' data-driven risk-management approach to cleaning verification methods uses analytical-recovery values for a model compound to place product-contact surfaces into groupings for analytical-method validation. The data generated during the studies supported the formation of three recovery groups to validate analytical swab methods. Groups 1–3 were represented by stainless steel 316L, cast iron, and Type III hard anodized aluminum, respectively. This approach allowed all surfaces to be considered during analytical-method validation and provided an objective mechanism to incorporate new surfaces into the strategy.

The benefits of this strategy are numerous. First, only three surfaces must be validated on each compound, which drastically minimizes the number of recovery values established to support the entire portfolio. Second, the strategy includes a way to add new materials of construction to the cleaning program if new equipment is purchased. Traditionally, all swab methods must be revalidated to incorporate the new surface. With this strategy in place, a model compound is evaluated, the new surface is grouped, and no changes to existing methods are required. Third, the strategy allows for a constant state of compliance. A relative recovery value is known for any material of construction for all equipment.

Because the grouping strategy is applied to a small fraction of the total surface area, no surface material of construction is ignored, each molecule undergoes a typical method validation, and the strategy places surfaces into groups conservatively. The authors believe that the strategy controls risks appropriately and that the data set given in this study scientifically supports the strategy of grouping materials of construction to support analytical methods within the cleaning program.


The authors would like to acknowledge the following colleagues at Eli Lilly: Gifford Fitzgerald, intern, for generating the swab-recovery data; Ron Iacocca, research advisor, for the SEM data; Sarah Davison, consultant chemist; Mike Ritchie, senior specialist; Mark Strege, senior research scientist; Matt Embry, associate consultant chemist; Kelly Hill, associate consultant for quality assurance; Bill Cleary, analytical chemist; and Laura Montgomery, senior technician, for their contributions and insightful suggestions throughout the project. In addition, Leo Manley, associate consultant engineer, provided the roughness measurements in support of this project.

GMP Consulting and the Pharmaceutical Industry

Many of the world's leading manufacturing centres of pharmaceutical and medical products have legislated that every pharmaceutical company under their jurisdiction follow GMP procedures. The details of the guidelines vary from country to country although they all follow the same general principles. GMP compliance assures the quality of medical products by governing the production and distribution stages of manufacture. It does this by following a series of assurances which monitor the production process.

o The manufacturing processes are plainly defined and controlled. All critical stages are validated to guarantee consistency and compliance with specifications.
o If there are any changes to these stages, they are evaluated. Changes that have an impact on the quality of the products are validated as required.
o All the instructions associated with each stage are written clearly and explicitly.
o Operators are trained to carry out and document procedures to the exact specification determined during the validation process.
o Records are kept, manually or by computers during manufacture which exhibit that all the steps required by the defined validation instructions were taken and that the number and quality of the drug was as expected. Deviations should be investigated and documented.
o Records of manufacture (including distribution) that detail the complete history of any individual batch should be retained in a comprehensible and accessible form in case it needs to be traced at any time.
o The distribution of the medicines should not add any risk to their quality.
o It should be possible to recall any batch of the product from the market, even if the batch has been opened.
o Complaints about medicines on the market are investigated, the causes of quality defects are examined, and the correct measures are taken so that all faulty products are recalled and the problem will not arise again.

GMP consulting is available to help companies set up their manufacture processes and to evaluate their business before and after GMP audits. The pharmaceutical industry relies on GMP consulting as a way to keep up with the complex and often confusing amount of legislation that covers the medical sector. They are particularly important if a business is expanding its operations in to foreign premises. In the United States, GMPs are governed by the Food and Drug Administration (FDA), the World Health Organisation (WHO) have their own version of GMP guidelines that are used by the pharmaceutical industries in developing countries, members of the European Union have their own GMPs, as do countries including Australia, Japan and Canada, which have their own sophisticated guidelines. In the UK, the Medicines Act (1968) covers most aspects of GMP and is known as 'The Rules and Guidance for Pharmaceutical Manufacturers and Distributors', or the 'Orange Guide' due to the colour of the document. This makes it very complicated for pharmaceutical companies with offices on more than one continent as they may need different processes in each base of manufacture.

The regulatory authorities in each country have the power to make unannounced inspections of premises and products to ensure that patients are not put at risk from any bad practices. In the US, they have the power to bring legal action against any company they find to be violating GMPs and the FDA actually publishes a list of companies and individuals who have been prosecuted or disciplined by them.

Good Manufacturing Practices are implemented to ensure that patients are not put at risk from complications caused by medicines. The role of a GMP consultant can vary with every company they work with, but their role is vital as it protects the health and safety of the general public. Professionals from the pharmaceutical industry join GMP consulting firms to share their knowledge and expertise with other companies to make sure that they are manufacturing safe products whilst trying to maximise their profits.

Essential Elements of a Quality Management System

A good quality management system in a pharmaceutical company can significantly improve the net profit status, high quality medicines for patients, less rework and recall which save more money, good work environment and compliance with local and international regulations.

Quality management is a philosophy. It takes management understanding, commitment and responsibility before introducing and implementing the concept. Once practiced a good quality management system slowly develop or reshape a sustainable organization culture that pays off rapidly.

The initial step of introducing a good quality management into a system is to know the essential elements of the quality system and clear study from where to start. Company objectives should be clearly understood. Policies should be prepared. Then comes the design of the process flow, validating the process, material flow and organization chart. When a good integration between people, process and material is achieved the next step is to putting the integrated system in a state of control. Any deviation from the controlled system must be analysed and corrected.

Some basic but essential elements of Quality Assurance as depicted in GMP guidelines and ISO 9001 guideline for pharmaceutical industry can be listed as: the Preparation of standard operating procedures of a complete system maintaining cGMP principles; Preparation and maintenance of effective change control of quality and master file documentation; Recording and management of manufacturing change control; Recording and reporting procedure of Deviations of your systems; Quality concern investigation process; Customer complaint investigation procedure; Quality audit procedures; Vendor assessment, evaluation and certification procedure; Quality control laboratory procedure, Rework procedures for the defective manufactured products; Procedures on training for manufacturing staffs and recall procedure.

Standard operating procedures and manuals should be written in details and referenced to relevant other documents, so a new starter within the organization should be trained easily and expected to perform as per procedure. The result will be a common standard of activities across the organization, good tractability of work flow, deviations and ease of corrective actions as necessary.

Standard Operating Procedure

You should prepare SOPs, forms, templates and manuals, which can be used immediately as the system runs. Forms and templates should be used for record keeping which your people can follow routinely.

Documentations - Classification, Definition and Approval

Quality and Technical/Master file documents to be created to build up a good quality management system for your manufacturing sites. Definition of documents, their classification, approval requirements and retention requirements should be understood.

Quality Documentation Management and Change Control

Procedures to be created on how to generate new quality documents or change control of existing documents, review of quality documents, satellite file management, role of document author, approver, document control officer and satellite file administrator. In this procedures you will also define the numbering systems of different quality documents like audit files, SOPs, forms, templates, manuals, training files, QA agreements, project files etc and their effective archiving system.

Preparation, Maintenance and Change Control of Master Documents

Procedures to be created which will particularly focus on the management of master file documents like specifications, control methods, raw materials, finished goods and packaging specification and test reports, formulation, stability files etc required to generate during the product registration in the market.

Deviation Report System

It is a regulatory requirement to capture all sorts of deviations evolves in your systems in order to maintain the continuous improvement of your processes and systems. Procedures should be created that describes how to categorize the deviations between production, audit, quality improvements, technical deviations, customer complaints and environmental, health and safety deviations. It should also describes the management responsibilities of initiating deviation, capturing data, analysis, investigation, determination of assignable cause/s, generation of management report and initiatives to be taken on corrective and preventative actions.

Vendor Selection and Evaluation

Procedures to be followed during the vendor assessment and vendor evaluation for purchasing of raw materials, critical and non critical packaging components, laboratory supplies, engineering supplies and imported finished goods from the vendor. These instructions are essential for approving prospective vendor.

Vendor Certification

This procedure aims to describe the process by which a vendor may be certified to supply materials or services. This procedure applies to vendors that supply a material or service to be used at any stage of manufacture by operations. Here you will describe the roles of each department in the process to certify an approved vendor.

Product Complaint Procedure

You should have strong procedure to cover the receipt, logging, evaluation, investigation and reporting system of all complaints received from customers for the marketed products. This procedure should contain step by step instruction to be followed during the customer complaint management like numbering of complaint, registering the complaint, evaluation, determination of assignable cause for the complaint deviation, implementation of corrective and preventative actions, trending of complaints and handling of counterfeit products.

Annual Product Review

Some countries require reports as Annual Product Review to sell your products into their market. So you have to create instructions on how to do annual product review, to evaluate data, trends and to identify any preventative or corrective action that would lead to product quality improvements and report them to management.

Rework Procedure

Procedure should contain the step by step instructions to be followed when the rework of an in-process or completed finished good is required. Product Identification and Traceability The purpose of this procedure is to define the method used for the identification of all contributing materials that could affect product quality and to ensure their full traceability.

GMP Audits

Procedure should be created to describe the process of planning, performing, reporting and follow-up of different audits for your systems like Internal Quality audit, Vendor audit, Environmental Health and Safety (EHS) audit, EHS workplace inspection, Housekeeping audit.

Evaluation of Batch Documentation and Release for Sale

This procedure should describe the process of collection, evaluation and record of batch related document generated during the production of a batch before an authorized person can release the batch for sale.

GMP Training

Effective GMP related training modules to be created for your manufacturing staffs. Training records and reports have to produce on each employee as justified.

Management and Control of Contract Work

There should have procedure to describe the management and control of contract work provided by the contractors for packaging and finished products for your company as well as control of contract works done by your company on behalf of others.

Quality Concern Investigation Process

Procedure should be made that contains instructions to follow when conducting Investigations collection of data and information, analysis, assigning root cause, determine corrective and preventive actions.

Auditing Process Validation


Validation is required to ensure that a process, system, material, method, product, piece of equipment, or personnel practice, will meet its intended purpose and function or allow functioning in a reliable, consistent manner. A firm derives little benefit if a thorough understanding of validation remains solely within the validation department.

After four decades of existence, validation is little better understood now than when it was first conceived--beyond the concept of "requiring a minimum of three runs". The term "validation" may differ in meaning from company to company. Validation is demonstrating and documenting that something does (or is) what it is purported to do (or be).

Challenge of the Auditor's Role

Resources to support validation may not be the best for adhering to compliance procedures. Start by understanding the SOPs pertinent to validation and, specifically, process validation. The auditor's role will be to examine executed protocols and reports against internal SOPs and external regulations. In addition to the SOPs governing Process Validation, the auditor needs to know if there have been other commitments against which a process validation should be checked.

o Prior internal audit commitments

o Customer audit commitments

o Internal program initiative commitments (e.g., GMP Program)

o FDA commitments (filing or inspection)

When are Process Validations (or Revalidations) Required?

During R&D, physical and chemical performance characteristics should be defined and translated into specifications, including acceptable ranges, which should be expressed in measurable terms. The validity of such specifications is verified through testing and challenge during development and initial production.

Validation of such processes need not be done before the Regulatory Filing (i.e., NDA, ANDA. Validation commitments may be included in the regulatory filing. The Validation Master Plan should include a periodicity (e.g., bi-annual) and specify revalidation when equipment, or other pertinent element, changes. When Annual Process Review (APR) indicates that "drift" is occurring, revalidation must be done.

FDA Regulations for process controls are included in Part 211--Current Good Manufacturing Practice for Finished Pharmaceuticals , Subpart F--Production and Process Controls , Section 211.100 Written procedures; deviations.

In part, these regulations require written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

Validation Types

There are several different types of validation approaches. The best is "Propsective", since it is planned for and is, therefore, most favored by the FDA.


assesses historical performance; traditionally requires more data, not permitted at some companies, but may be necessary for products that have been in production for a long time and pre-dated current requirements for validation.


gathers data as runs are executed; less than ideal due to lack of pre-planning


planned protocol, pre-validation tasks ensured; FDA-favored

Process Validations (Process Qualifications)

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. The intent is to demonstrate that a process repeatedly yields product of acceptable quality. A minimum of 3 consecutively successful cycles--on a given piece of equipment using a specific process--constitutes process and equipment validation. Not only is the process under scrutiny, but the piece of equipment used to deliver that process is as well. Process operating limits should be tested, but not edge of failure. "Robustness" and "worst case" are common goals.

Activities that Occur in Advance of Process Validation

Analytical methods must be validated. Processing parameters and conditions must be specified and approved. There must be an availability of clear and detailed SOPs and Manufacturing Batch instruction which avoid the use of subjective criteria and wide processing ranges (e.g., mix gently for 10 - 60 minutes).

Upstream Tasks to Minimize Variability

Check to ensure that tasks are completed which could add variability to the validation, such as:

-Employee training

-Equipment IQ, OQ, Calibration & Maintenance

-Component specifications

-Environmental requirements (temperature, humidity, controlled air quality)

-Qualification of key production materials

Importance of the Protocol

It is a commitment established by the parties involved with the activity. It involves a description of the activity, the proposed and agreed-upon manner to achieve that goal, the number of runs required to achieve that goal, and the acceptance criteria. It is an FDA expectation that all validation protocols be approved before execution. Typical sources for approval are the department responsible for protocol preparation, the department where the equipment will be installed and the quality group.

Protocol & Acceptance Criteria

Product quality attributes must be detailed in the protocol. "Acceptance Criteria" are often the established Product Specifications. Validation should not be used to establish or optimize processing parameters and specifications. Acceptance Criteria may be more stringent, but should never be less demanding, than the Product Specifications. Watch for subjective statements, since they cannot be validated. Example: ...continue to add water until you have a suitable granulation..."

Test conditions should encompass upper and lower processing limits which place the most stress on the system. Key process variables should be monitored and documented. Data analysis should establish variability of process parameters.

FDA's Perception of the Role of the Quality Unit

Those involved in validation must understand what responsibilities the FDA holds the quality unit accountable for. Ensure that any additional requirements from the quality unit have been met by the executed validation--especially additional testing, repeating questionable tests, and providing more rationale.

FDA Regulations for sampling and testing are included Part 211--Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart F--Production and Process Controls, Section 211.110 Sampling and testing of in-process materials and drug products

In part, these regulations require that written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate: tablet or capsule weight variation; disintegration time; adequacy of mixing to assure uniformity and homogeneity; dissolution time and rate; clarity, completeness, or pH of solutions.

Failure to Meet Acceptance Criteria

Unless the acceptance criteria are met, or there is a sound justification for not meeting them, the goal is not achieved and the validation has failed. When protocol failure occurs, it is customary to conduct an investigation. The investigation should: identify the assignable cause, identify corrective actions, and restart the activity. The importance of this investigation and identification of corrective actions cannot be overstressed. If the investigation does not identify an assignable cause for the failure, the validation must be restarted.

Validating a Transferred Process

In the age of multi-national corporations, it is not uncommon for an R&D unit to be located in one part of the nation (or globe) and the manufacturing unit in another. Thus, when a process is transferred from one place to another, a number of technology transfer points and documents are generated as prospective validation in order to proceed with validation through the various steps of product development. There are many departments involved and they are usually isolated units. Confusion results unless communication is good. Often, a project management team approach will facilitate inclusion of all affected units and identification of all of the steps involved.

Validation of Transferred Technology

Audit checklists can be used to ensure that important elements of the transferred process were not overlooked or misunderstood. Appropriate participants should have approved the protocol and also the final report. If it isn't clear to the auditor, it won't be clear to FDA.

Questions Often Asked During Technology Transfer

Raw Materials

Do specifications exist?

Do they make sense?

Are the test methods reliable?

Are the specifications needed?

What should be specified but isn't?

What is the source of raw materials?

Are there more sources?

What is the grade to be used?

Are the grades interchangeable?


Does the plant have the proper equipment?

Are the batch size and equipment matched?

Does an alternate supplier exist?

Can the equipment in the plant be used--even though the principle of operation is not yet specified?

Process Parameters

Are the set points too narrow?

Are the set points too wide?

How were the set points determined?


How do I sample?

What do I sample?

Where do I sample?

Why should I sample?

How much sample should I take?

What does the data mean after it is obtained?

Final Product

How were the specifications set?

A Standard Procedure For Quality Assurance Deviation Management

What is a Deviation:
A Deviation is a departure from standard procedures or specifications resulting in non-conforming material and/or processes or where there have been unusual or unexplained events which have the potential to impact on product quality, system integrity or personal safety. For compliance to GMP and the sake of continuous improvement, these deviations are recorded in the form of Deviation Report (DR).

Types of Deviations:
1. Following are some examples of deviations raised from different functional areas of business:
2. Production Deviation - usually raised during the manufacture of a batch production.
3. EHS Deviation - raised due to an environmental, health and safety hazards.
4. Quality Improvement Deviation - may be raised if a potential weakness has been identified and the implementation will require project approval.
5. Audit Deviation - raised to flag non-conformance identified during internal, external, supplier or corporate audits.
6. Customer Service Deviation - raised to track implementation measures related to customer complaints.
7. Technical Deviation - can be raised for validation discrepancies. For example: changes in Manufacturing Instruction.
8. Material Complaint - raised to document any issues with regards to non-conforming, superseded or obsolete raw materials/components, packaging or imported finished goods.
9. System Routing Deviation - raised to track changes made to Bill of materials as a result of an Artwork change.

When to Report Deviation:
A Deviation should be raised when there is a deviation from methods or controls specified in manufacturing documents, material control documents, standard operating procedure for products and confirmed out of specification results and from the occurrence of an event and observation suggesting the existence of a real or potential quality related problems.

A deviation should be reported if a trend is noticed that requires further investigation.
All batch production deviations (planned or unintended) covering all manufacturing facilities, equipments, operations, distribution, procedures, systems and record keeping must be reported and investigated for corrective and preventative action.

Reporting deviation is required regardless of final batch disposition. If a batch is rejected a deviation reporting is still required.

Different Levels of Deviation Risks:
For the ease of assessing risk any deviation can be classified into one of the three levels 1, 2 & 3 based on the magnitude and seriousness of a deviation.

Level 1: Critical Deviation
Deviation from Company Standards and/or current regulatory expectations that provide immediate and significant risk to product quality, patient safety or data integrity or a combination/repetition of major deficiencies that indicate a critical failure of systems

Level 2: Serious Deviation
Deviation from Company Standards and/or current regulatory expectations that provide a potentially significant risk to product quality, patient safety or data integrity or could potentially result in significant observations from a regulatory agency or a combination/repetition of "other" deficiencies that indicate a failure of system(s).

Level 3: Standard Deviation
Observations of a less serious or isolated nature that are not deemed Critical or Major, but require correction or suggestions given on how to improve systems or procedures that may be compliant but would benefit from improvement (e.g. incorrect data entry).

How to Manage Reported Deviation:
The department Manager or delegate should initiate the deviation report by using a standard deviation form as soon as a deviation is found. Write a short description of the fact with a title in the table on the form and notify the Quality Assurance department within one business day to identify the investigation.

QA has to evaluate the deviation and assess the potential impact to the product quality, validation and regulatory requirement. All completed deviation investigations are to be approved by QA Manager or delegate. QA Manger has to justify wither the deviation is a Critical, Serious or Standard in nature. For a deviation of either critical or serious nature QA delegate has to arrange a Cross Functional Investigation.

For a standard type deviation a Cross functional Investigation (CFI) is not necessary. Immediate corrective actions have to be completed before the final disposition of a batch. Final batch disposition is the responsibility of Quality Assurance Department.

If a critical or serious deviation leads to a CFI, corrective and preventive actions should be determined and follow up tasks should be assigned to area representatives. Follow up tasks should be completed within 30 business days of the observation of deviation. If a deviation with CFI can not be completed within 30 business days, an interim report should be generated detailing the reason for the delay and the progress so far.

After successful completion of the Follow up tasks Deviation should be completed and attached with the Batch Report /Audit report/ Product complaint report /Safety investigation report as appropriate.

What To Check During The Deviation Assessment:
QA delegate has to conduct a primary Investigation on the deviation reported and evaluate the following information

1. Scope of the deviation - batch affected (both in-process and previously released)
2. Trends relating to (but limited to) similar products, materials, equipment and testing processes, product complaints, previous deviations, annual product reviews, and /or returned goods etc where appropriate.
3. A review of similar causes.
4. Potential quality impact.
5. Regulatory commitment impact.
6. Other batches potentially affected.
7. Market actions (i.e. recall et

Concept of Validation

According to GMP definition Validation is "Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes."

Appropriate and complete documentation is recognized as being crucial to the validation effort. Standard Operating Procedures (SOPs), manufacturing formulae, detailed batch documentation, change control systems, investigational reporting systems, analytical documentation, development reports, validation protocols and reports are integral components of the validation philosophy. The validation documentation provides a source of information for the ongoing operation of the facility and is a resource that is used in subsequent process development or modification activities.

All validation activities will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified.

A revalidation program should be implemented based on routine equipment revalidation requirements and on the Change Control Policy.

Types of Validation

Prospective validation
Establishing documented evidence that a piece of equipment/process or system will do what it purports to do, based upon a pre-planned series of scientific tests as defined in the Validation Plan.

Concurrent validation
Is employed when an existing process can be shown to be in a state of control by applying tests on samples at strategic points throughout a process; and at the end of the process. All data is collected concurrently with the implementation of the process until sufficient information is available to demonstrate process reproducibility.

Retrospective validation
Establishing documented evidence that a process does what it purports to do, based on review and analysis of historical data.

Design Qualification (DQ)
The intent of the DQ is met during the design and commissioning process by a number of mechanisms, which include:

- Generation of User Requirement Specifications
- Verification that design meets relevant user requirement specifications.
- Supplier Assessment /Audits
- Challenge of the design by GMP review audits
- Product Quality Impact Assessment
- Specifying Validation documentation requirements from equipment suppliers
- Agreement with suppliers on the performance objectives
- Factory Acceptance Testing (FAT), Site Acceptance Testing (SAT) & commissioning procedures
- Defining construction and installation documentation to assist with Installation Qualification (IQ).

Installation Qualification (IQ)
IQ provides documented evidence that the equipment or system has been developed, supplied and installed in accordance with design drawings, the supplier's recommendations and In-house requirements. Furthermore, IQ ensures that a record of the principal features of the equipment or system, as installed, is available and that it is supported by sufficient adequate documentation to enable satisfactory operation, maintenance and change control to be implemented.

Operational Qualification (OQ)
OQ provides documented evidence that the equipment operates as intended throughout the specified design, operational or approved acceptance range of the equipment, as applicable. In cases where process steps are tested, a suitable placebo batch will be used to demonstrate equipment functionality.
All new equipment should be fully commissioned prior to commencing OQ to ensure that as a minimum the equipment is safe to operate, all mechanical assembly and pre-qualification checks have been completed, that the equipment is fully functional and that documentation is complete.

Performance Qualification (PQ)
The purpose of PQ is to provide documented evidence that the equipment can consistently achieve and maintain its performance specifications over a prolonged operating period at a defined operating point to produce a product of pre-determined quality. The performance specification will reference process parameters, in-process and product specifications. PQ requires three product batches to meet all acceptance criteria for in-process and product testing. For utility systems, PQ requires the utility medium to meet all specifications over a prolonged sampling period.

The PQ documentation should reference standard manufacturing procedures and batch records and describe the methodology of sampling and testing to be used.

What Gets Validated
All process steps, production equipment, systems and environment, directly used for the manufacture of sterile and non sterile products must be formally validated.

All major packaging equipment and processes should be validated. This validation is less comprehensive.
All ancillary systems that do not directly impact on product quality should be qualified by means of a technical documentation of the extent of the system and how it operates.

- Manufacturing Area Design.
- Personnel and material flow etc.

Process and Equipment Design
Process steps and equipment description. i.e. Dispensing, Formulating, Packaging, Equipment washing
and cleaning. etc

Utility Systems Design
Raw/purified steam, Purified water, Compressed Air, Air conditioning system, Vacuum, Power supply, Lighting, Cooling water, Waste etc

Computerized Systems Design
Information system, Laboratory automated equipments, Manufacturing automated equipments, Electronic records etc

Cleaning Validation (CV)
CV provides documented evidence that a cleaning procedure is effective in reducing to pre-defined maximum allowable limits, all chemical and microbiological contamination from an item of equipment or a manufacturing area following processing. The means of evaluating the effectiveness of cleaning involves sampling cleaned and sanitized surfaces and verifying the level of product residues, cleaning residues and bacterial contamination.

The term CV is to be used to describe the analytical investigation of a cleaning procedure or cycle. The validation protocols should reference background documentation relating to the rationale for "worst case" testing, where this is proposed. It should also explain the development of the acceptance criteria, including chemical and microbial specifications, limits of detection and the selection of sampling methods.

Method Validation (MV)
MV provides documented evidence that internally developed test methods are accurate, robust, effective, reproducible and repeatable. The validation protocols should reference background documentation relating to the rationale for the determination of limits of detection and method sensitivity.

Computer Validation
Computer Validation provides documented evidence to assure systems will consistently function according to their pre-determined specifications and quality attributes, throughout their lifecycle. Important aspects of this validation approach are the formal management of design (through a specification process); system-quality (through systematic review and testing); risk (through identification and assessment of novelty and critical functionality) and lifecycle (through sustained change control).

Where equipment is controlled by embedded computer systems, elements of computer validation may be performed as part of the equipment IQ and OQ protocols.

General process, cleaning and methodology validation concepts are described in this article with a special view to pharmaceutical industry

Thursday, August 26, 2010



1.1 To establish the system for Validation of Moist heat Sterilization.


2.1 It is applicable for Injectables Department.


3.1 Quality Control Manager
3.2 Microbiologist
3.3 Production Officer (concerned)


Autoclave tape is affixed to all trolleys and Effectiveness of Autoclavation is determined by the change in color of the tape.


Prepare the media as directed on the label.

1. Fluid Thioglycollate Medium ( For Bacteria )
2. Tryptic Soy Broth ( For Fungi )

Sterilize in an autoclave and incubate at required temperatures for at least 24 hours.

Inoculate the Fluid Thioglycollate Medium with Staphylococcus aureus and Tryptic Soy Broth, with Candida Albicans.
Keep one portion of each of the un-inoculated media un-opened ( Medium Control.)
Keep one portion of each of the inoculated media, un-opened. ( Culture Control.)
Place the Rest of the Inoculated tubes at different position in the Autoclave chamber, with the product undergoing process of Autoclavation.
After completion of the process incubate the media at their respective temperature.
Fluid Thioglycollate Medium ( For Bacteria ) at 30 – 35º C
Tryptic Soy Broth ( For Fungi ) at 20 – 25º C
Incubate the samples and controls for 14 days and observe.

Media Control: Must NOT show any growth to ensure the sterilization of media.
Culture Control: Must show the growth to ensure the growth promoting activity of the media.


Thermocouples are used for the temperature validation of autoclave, which are calibrated before use in autoclave temperature validation.
Calibrated thermocouples are placed at 18 different specified locations in the autoclave to have true picture of temperature conditions inside the autoclave. They are placed at front, middle, end, top, centre and bottom of the autoclave.
Thermocouples should not show temperature deviation by + 0.5°C, as compared to actual panel temperature of autoclave.
Hence process is validated.
5. Frequency / Year

Validation of Moist heat Sterilization should be conducted Once in a Year.



1.1 To establish the system for Validation of Sterilization of uniform.


2.1 It is applicable for Injectables Department.


3.1 Quality Control Manager

3.2 Microbiologist

3.3 Production Officer (concerned)



Autoclave tape is affixed to the uniform wrapped in butter paper and Effectiveness of its sterilization is determined by the change in color of the tape.


Prepare the media as directed on the label.

1. Fluid Thioglycollate Medium ( For Bacteria )

2. Tryptic Soy Broth ( For Fungi )

Sterilize in an autoclave and incubate at required temperatures for at least 24 hours.

Inoculate the Fluid Thioglycollate Medium with Staphylococcus aureus and Tryptic Soy Broth, with Candida Albicans.

Keep one portion of each of the un-inoculated media un-opened ( Medium Control.)

Keep one portion of each of the inoculated media un-opened. ( Culture Control.)

Place the Rest of the Inoculated tubes along with the uniforms in the Autoclave chamber.

After completion of the process incubate the media at their respective temperature.

Fluid Thioglycollate Medium ( For Bacteria ) at 30 – 35º C

Tryptic Soy Broth ( For Fungi ) at 20 – 25º C

Incubate the samples and controls for 14 days and observe.


Media Control: Must NOT show any growth to ensure the sterilization of media.

Culture Control: Must show the growth to ensure the growth promoting activity of the media.


5. Frequency / Year

Validation of uniform Sterilization should be conducted Once in a Year.