6.3 Operational Process Validation and Production Change Order Control

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

Validation and equipment qualification; when "identical" really isn't.

Must firms validate use of non-USP testing methods for USP medical gases? 

Does FDA have a policy regarding use of the "Matrix" or "Family" approaches to process validation?

Has FDA established a required number of runs to be performed during Operational Qualification (OQ) testing? If a firm qualifies one type and model of equipment, can it be used in a different process without additional qualification?

If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?

What records do the CGMPs require a firm to examine under the 211.180(e) periodic review? Must such records be stamped with a review or expiration date?

Is testing rinse solution alone enough to support residue determinations for cleaning validation?

Do the CGMP regulations specify how frequently firms must review their SOPs? 

What should investigators look for when inspecting a firm's cleaning validation program?

Does FDA have impurities acceptance limits for cleaning validation and subsequent cleaning verification?

Do CGMPs require validation of computerized air separation plants/units (ASU)? Is this new?

What cleaning and process validation do the CGMPs require for production of a bio-batch, where only a single lot has been made?

In the performance of system suitability, do all replicate standard injections have to be completed before any analyte sample injections are made?

Are tablet press RPMs important enough to be a factor in process  validation?

Policy Questions on Cleaning Validation:  What is the level of detergent residue that would be acceptable  to FDA? What is the basis for arriving at this level, if any?

Policy Questions on Cleaning Validation:  If the ability of a procedure to clean a piece of equipment made of a particular material, such as 316 stainless steel, is shown to be acceptable and validated, can that "material" specific cleaning procedure be used without "extensive" validation for other pieces of equipment and compounds?

Validation and equipment qualification; when "identical" really isn't.

Reference: 
21 CFR 211.100, Written procedures, deviations; 
Guideline On General Principles of Process Validation, May, 1987

As explained in the 1987 validation guideline, the general requirement for process validation is contained in section 211.100 of the CGMP regulations which states that "[T]here shall be 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." 

The validation guideline addresses several general principles of equipment suitability. For example, installation qualification is described as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. Installation qualification includes examination of equipment design, determination of calibration, maintenance, and adjustment requirements, and identifying critical equipment features that could affect the process and product.  Another principle is that equipment is evaluated and tested to verify that it is capable of operating satisfactorily within the required process operating limits and that actual production conditions, including "worst case" situations, are simulated. The guideline cautions that "[I]n assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier…"

The guideline further states that each specific process should be appropriately qualified and validated, noting the inherent danger in relying on perceived similarities between products, processes, and equipment.

The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment, and the problems that may result when firms fail to verify equipment supplier representations.

A pharmaceutical firm used two blenders to produce a tablet. Both blenders were from the same equipment manufacturer, had the same model number and same design. Although one blender was older than the other, the supplier told the drug manufacturer that the units were "identical." The drug manufacturer took the claim at face value and did not include the older blender as part of its process validation.

The drug company marketed about 100 lots of tablets made using the old blender. In testing retain samples, the company found that some lots failed the content uniformity specification.

The firm's investigation traced the out of specification lots to one of the two "identical" blenders, namely the old one. The pharmaceutical firm's own investigation found the older blender to have a slightly smaller capacity and different RPM (revolutions per minute) operational characteristics when run at the same settings as the newer blender.

Subsequently, the firm recalled its total production of the product it made using the older blender. This extensive recall involved multiple strengths of product totaling approximately one half million bottles from U.S. and foreign consignees. The firm plans to qualify the old blender using production size lots.

In light of this case study, during your audits of a firm's process validation, it would be appropriate to determine if the firm's validation protocol includes equipment qualification for all units of significant equipment, even where multiple units are supposedly "identical." Moreover, as explained in the validation guideline, the validation should reflect production size lots.

Contact for further information: Michael J.Verdi, HFD-301, 301-594-2456; e-mail: verdim@cder.fda.gov 

Must firms validate use of non-USP testing methods for USP medical gases? 

Reference: 21 CFR 211.160, General requirements [Subpart I, Laboratory Controls]; 
211.165(e), Testing and release for distribution; 
211.194, Laboratory records 

Yes. The CGMP regulations, at sections 211.165(e) and 211.194(a)(2), require a firm or individual utilizing a non-U.S.P. testing methodology to perform a validation study establishing and documenting the accuracy, sensitivity, specificity, and reproducibility of the test method employed. 

This would include paramagnetic analyzers, handheld analyzers, pressure differential methods, etc.; all would be required to undergo validation. In addition, any firm using one of these non-U.S.P. testing methods must have complete documentation, per 211.194, for the entire validation study, not just the data.

Contact for further information: Duane Sylvia, HFD-325, 301-594-0095, e-mail: sylviad@cder.fda.gov .

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 2) June, 1999.

Does FDA have a policy regarding use of the "Matrix" or "Family" approaches to process validation?

Reference: 
21 CFR 211.100, Written procedures; deviations; 
211.110, Sampling and testing of in-process materials and drug products; 
May 1987, Guideline on General Principles of Process Validation

No. The CGMP regulations, at section 211.110, require a manufacturer 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."  Although some guidance is presented in the May 1987 "Guideline on General Principles of Process Validation," CDER has not published any formal written policy on the "matrix" or "family" approaches to process validation. 

Nonetheless, because the general principle is to validate a drug manufacturing "process," in theory it may be possible for a manufacturer that uses the same "process" for several related products to develop a scientifically sound validation plan for that process, rather than different plans for each product manufactured by that process.

We have reviewed several plans that use a "matrix approach," and have received inquiries regarding a "family approach" to process validation. Within these proposals, a "matrix approach" generally means a plan to conduct process validation on different strengths of the same product, whereas the term "family approach" has been used to describe a plan to conduct process validation on different, but similar products. In the cases we're aware of, both approaches generally call for a plan to validate the process using a minimum number of production batches of each strength or product. Either approach may be in accord with CGMP if the study demonstrates that the process is consistent for all the strengths or products involved. It is important that any such validation plan be designed to evaluate all sources of variation in the products manufactured by the process.

Each plan should be evaluated on a case by case basis and it is up to the manufacturer to develop and justify the appropriate matrix according to the specific similarities and differences in the different strengths or different products. For example, if there are significant differences in the equipment or process, we would expect that each strength/product would need to be validated separately.

The agency has not yet established its current thinking about the principles of the matrix or family approach; thus, our limited experience cannot yet be broadly extrapolated to applied CGMP. Those principles are gradually emerging, though, and we anticipate addressing them thoroughly in future guidance documents.

Contact for further info: John Dietrick, HFD-325, 301-594-0098; e-mail: dietrickj@cder.fda.gov .

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.

Has FDA established a required number of runs to be performed during Operational Qualification (OQ) testing? If a firm qualifies one type and model of equipment, can it be used in a different process without additional qualification?

Reference: 
21 CFR 211.100, Written procedures; deviations; 
May 1987, Guideline on General Principles of Process Validation

Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ), along with other similar terms, are commonly used in the pharmaceutical industry to discuss the generally accepted concept that a firm should qualify equipment and systems as part of validating a manufacturing process. The FDA Guideline on General Principles of Process Validation does not use the term Operational Qualification. It defines Installation Qualification as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. This includes IQ and OQ. The FDA Guideline also defines Process Performance Qualification as establishing confidence that the process is effective and reproducible.

The guideline states that "it is important that equipment qualification simulate actual production conditions, including those which are 'worst case' situations," and that "tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results."

Regarding the first question, the often-cited "three consecutive batch" recommendation is intended for process validation rather than for equipment qualification. FDA has not recommended any specific number of "runs" for equipment qualification, but expects multiple tests to simulate actual operating ranges and to establish consistency.

As to the second question, FDA expects Installation Qualification on each piece of equipment to document that it is installed correctly and operates consistently according to established limits and tolerances. Operational Qualification should also be performed for each different use of the equipment or system to document the suitability for that use, but would not be required for additional pieces of the same type/model of equipment when used in the same process. Process Performance Qualification would also not be required for each piece of the same type/model of equipment used in the same process, provided installation qualification has been performed.

Contact for further info: John Dietrick, HFD-325, 301-594-0098; e-mail: dietrickj@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework section 4.5.

If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?

Reference: 
21 CFR 211.22(a & b), Responsibilities of quality control unit, 
21 CFR 211.160(b), General requirements [Subpart I—Laboratory Controls]; 
21 CFR 165, Testing and release for distribution (sic); 
Draft Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production, 9/30/98; 
21 CFR 211.194, Laboratory records

There are a number of possible scenarios under this question. Under CGMP, FDA would expect the contract laboratory to have a quality control unit. The lab's QC unit has the CGMP responsibility to ensure the analytical results obtained are accurate for the tested material. This means the contract laboratory needs to investigate any OOS result with the purpose of ascertaining such accuracy. This would be accomplished by ensuring that personnel performed the tests properly using: (1) The current validated analytical procedure; (2) correct reagents and reference standards; and, (3) equipment that has been properly maintained and calibrated.

There are basically two possible results of the lab's investigation.

1) If the lab determines the analyst made an error, or that instrument malfunction occurred, the test results may be invalidated. The analysis would be re-run according to the approved analytical method. The re-run test results would be considered the original results, and these results would be reported to the manufacturer. The lab does not have a CGMP obligation to report the initial (invalidated) results to the manufacturer; however, the lab must, per 211.194, retain the records pertaining to those initial results.

2) If the laboratory determines that there was no analyst error, and that no instrument malfunction occurred, then the results must be considered accurate and reported to the pharmaceutical manufacturer.

In the event of outcome number two, the pharmaceutical manufacturer would have analytical results indicating the material does not meet its specifications. Under CGMP, an investigation must take place. The manufacturer is responsible for investigating the production process to determine if any mistakes were made--things to consider could include charge-in of components, mixing times, and quality of components. Storage conditions of the analyzed material, and the sampling method used also need to be reviewed to ascertain whether the tested material might not have been representative of the batch.

If the manufacturer's investigation fails to find a cause, it might also consider whether the contract laboratory is suspect (i.e., if perhaps the lab made an unrecognized error.) The CGMPs do not, however, explicitly require the manufacturer to extend its investigation to the lab's operations. However, it is considered CGMP for manufacturers to qualify their contract laboratories.  At comment paragraph 94 of the September 29, 1978 CGMP revisions, 43 FR 45034, the agency said "[a] manufacturer does have a responsibility, however, to see that the outside laboratory used is qualified to do the work and that the work is performed satisfactorily." 

As part of its investigation, the manufacturer might take the opportunity to requalify the contract laboratory, or may consider changing contract laboratories. Retesting could also be part of this process.

It must be stressed that in this situation the manufacturer has information that the batch does not meet its quality standards, and unless that information can be invalidated, it must be used to reach a batch disposition decision, namely, whether to destroy the batch, or reprocess it to bring it into compliance. 

Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework sections 1.1, 4.3, 4.4, 5.2, 5.5, 6.4, and 7.2.

What records do the CGMPs require a firm to examine under the 211.180(e) periodic review? Must such records be stamped with a review or expiration date?

Reference: 
21 CFR 211.180(e), General requirements, Subpart J - Records and Reports; 
Federal Register 1/20/95 (60 FR 4087) Final Rule, Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; Amendment of Certain Requirements for Finished Pharmaceuticals

Section 211.180(e) states that, "Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures." (Emphasis added) 

This section is intended to require firms to perform a systematic review of data relating to product specifications and manufacturing and control procedures to determine if changes are warranted. Data that indicate a need for such changes can be contained within a broad range of records. That's why the regulation is explicit in referring to records required "by this part"; part means 21 CFR part 211. The data must be in a retrievable form so firms can use the information as needed when conducting the evaluation. This does not mean that every record a firm creates to meet a part 211 requirement must be reviewed. Rather, records specified by 211.180(e)(1) and (2) must always be part of that review whereas other records would be reviewed as indications for needed change arise.

The regulations give firms a great deal of latitude in exactly how they conduct periodic evaluations. However, the CGMPs establish key principles. First, the purpose of the review itself is to determine if changes in specifications or manufacturing or control procedures are needed. Second, the review both corrects and prevents product quality problems; that's why the regulations specify that reviewed batches represent those that have been both approved and rejected. [Note that although 211.180 states that "batches" and applicable associated records are to be reviewed, the preamble to the 1995 final rule that last modified this section clearly indicates that "batches" means "batch records."] In other words, indications of the need for change can be contained in records relating to conforming and non-conforming products. For example, production records for conforming lots may nonetheless indicate that a process is drifting out of control. Third, the review must be conducted at least annually.

A broad CGMP principle that runs throughout the regulations is the concept of redundant checks and balances to ultimately ensure product quality. The 211.180 periodic review provides that balance with respect to change control because, in addition to having an effective change control system, reviews of records that establish product specifications or manufacturing or control procedures can help firms maintain the currency and accuracy of such things as: (1) Cross references to other documents and standards; (2) materials' specifications (e.g., ensuring they match what's in a firm's most recent NDA submission or USP monograph); (3) equipment references (e.g., too generalized a manufacturing instruction to use a "suitable mixer" where different types and sizes are at hand would need to be made specific); (4) process step sequencing; (5) process step parameters; and, (6) acceptance criteria. Especially where a firm makes significant or frequent changes, this complex matrix of interrelated instructions and specifications can make change control difficult and may result in operators using outdated or otherwise incorrect procedures or standards to make medicine. We have encountered situations where an effective periodic review could have prevented such problems.

The regulations mandate that certain core records most likely to indicate a need for changes be reviewed. Included are records: (1) For each drug product covering complaints, recalls, returned or salvaged products and discrepancy/failure investigations conducted under section 211.192; and, (2) applicable to, and associated with, a representative number of batches produced over the review period. Master production records would be part of the second (batch related) grouping. Also included in that grouping would be other records that establish product specifications or manufacturing or control procedures. These records are intrinsically relevant to the review because: (1) Per CGMP, batches must be made according to those procedures and specifications; and, (2) those very procedures and specifications are what may need to be modified. Because those records may in and of themselves hold indications that changes are needed (e.g., outdated/superseded instructions), a meaningful assessment of the need for change would thus be impossible without at least a minimal review of those records. Be aware that some firms may call some records in this latter category standard operating procedures (SOPs) (e.g., how to collect an in-process sample).

Although we expect that the primary indicators of the need for change reside in those records explicitly identified in 211.180(e)(1) and (2), other records may also hold indications of the need for change. Although the CGMPs don't specify those records, any included in the review need to be identified in a firm's review procedures. During your inspections, be aware of evidence indicating that a firm's review procedures may be inadequate by virtue of failing to consider relevant records that hold change indicators, especially where product defects can be attributable to a failure to make needed changes.

Examples of records we would not normally expect to hold indicators of the need to change product specifications or manufacturing or control procedures include written procedures for component purchasing methods and product distribution recordkeeping.

CGMPs don't require that records be affixed with review dates, nor expiration dates. Records that establish product specifications or manufacturing or control procedures (including such records that firms call SOPs) can therefore continue in effect until superseded or discontinued.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 4) December, 1998.
This same text is also reprinted in Framework sections 1.2 and 1.5.

Is testing rinse solution alone enough to support residue determinations for cleaning validation?

Reference: FDA Guide to Inspections of Validation of Cleaning Processes, July 1993

While it is understood that rinse samples are capable of sampling larger surface areas, particularly ones which are difficult to access, for the purposes of cleaning validation, rinse samples alone would not be acceptable unless a direct measurement of the residue or contaminant has been made. One disadvantage of rinse samples is that the residue or contaminant may not be soluble or may adhere to the equipment. Some firms use both swab samples, where feasible, and rinse samples during the course of their cleaning validation. 

For routine equipment cleaning after validation, some firms may be able to justify use of rinse samples to demonstrate the process continues to consistently clean the equipment.

FDA has compared rinse samples to that of a "dirty pot analogy." When evaluating the cleaning of a dirty pot, the rinse water is not what is looked at to see if the pot is clean. 

The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently clean the equipment to a predetermined limit; the sampling and analytical test methods should be scientifically sound and provide adequate scientific rationale to support the validation.

Contact for further info: Patricia L. Alcock, HFD-322, (301)594-0095; e-mail: alcockp@cder.fda.gov 

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 4) December, 1998.

Do the CGMP regulations specify how frequently firms must review their SOPs? 

References: 
See 21 CFR 211.180(e), General requirements [Subpart J - Records and Reports]

Yes. At the referenced section, the CGMP regulations call for at least an annual evaluation of each drug product's quality standards to determine the need for changes in product specifications or manufacturing or control procedures. The rule also requires firms to establish and follow written procedures for conducting those evaluations. Such an evaluation would be incomplete if the standard operating procedures for production and process controls were themselves not reviewed.

During your establishment inspections, when auditing for compliance with section 211.180, determine if the firm has established, and is following, those evaluation procedures. Also check to see if the procedures call for reviewing SOPs.

Keeping SOPs current can be a challenging task when manufacturers make frequent changes or have a matrix of SOPs that cross-reference each other. Ensuring that employees are furnished with current versions of SOPs can be problematic. Therefore, during your audits, you might compare dates and version numbers of SOPs that a firm's operators use, against a master list of current SOPs. Discrepancies should be noted as objectionable conditions.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 3) September, 1998.
This same text is also reprinted in Framework sections 1.2 and 1.5.

What should investigators look for when inspecting a firm's cleaning validation program?

Reference: 
21 CFR 211.67, Equipment cleaning and maintenance; 
21 CFR 211.100, Written procedures; 
21 CFR 211.160, Laboratory controls; 
FDA Guide to Inspections of Validation of Cleaning Processes, July, 1993

The objective of cleaning validation is to ensure that a specific cleaning process will consistently clean to predetermined limits so as to prevent contaminants (product or cleaning process related) from adversely affecting the safety and quality of the next product manufactured.

As stated in the Guide to Inspections of Validation of Cleaning Processes, determine if firms have a written, well established and validated cleaning program. Basic steps include the development of a sensitive, accurate and precise analytical method for the determination of an acceptable limit, something necessary for any analytical test method developed in conformance with CGMPs. In addition, as discussed in the guide, determine if firms have and follow specific written procedures as to how cleaning will be performed, as well as how the cleaning validation will be conducted (including sampling procedures and analytical methods). Determine if the validation protocol addresses different sampling surface types, hardest to clean areas, and specific equipment, including utensils. FDA expects the validation studies will be completed in accordance with written protocols and that the final validation report will include the appropriate conclusions with management concurrence. Performing testing of cleaned equipment, in accordance with written procedures, would be consistent with 21 CFR 211.67(b).

Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail: alcockp@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 4.3.

Does FDA have impurities acceptance limits for cleaning validation and subsequent cleaning verification?

Reference: 
21 CFR 211.67, Equipment cleaning and maintenance; 
21 CFR 211.176, Penicillin contamination; 
International Committee on Harmonization (ICH) Guideline on Impurities in New Drug Substances, Q3A, May, 1997

FDA has always been concerned with the issue of contamination and cross contamination. Such contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants.

Except for penicillin, FDA has not established standard acceptance limits for cleaning validation. Due to the wide variation in both equipment and products produced, it would be unrealistic for the agency to determine a specific limit. In the CGMP context, however, firms need to establish limits that reflect the practical capability of their cleaning processes, as well as the specificity of the analytical test method.

We have found that some firms have incorrectly applied as their acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process or related compounds and not extraneous impurities caused by cross contamination. It is important that acceptance limits reflect the capability of the cleaning process.

When determining the acceptance limit, relevant factors generally include: (1) Evaluation of the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of the contaminant in the rinses; (4) limit of detection of the analytical test method; and, (5) visual examination. While we suggest that these factors be considered, relying only on visual examination would not be scientifically sound.

Contact for further info: Patricia L. Alcock, HFD-322, (301) 594- 0095; e-mail: alcockp@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in framework section 4.3.

Do CGMPs require validation of computerized air separation plants/units (ASU)? Is this new?

Reference: 

21 CFR 211.68(a) Automatic, mechanical, and electronic equipment.

Yes, those systems must be validated, per CGMPs. This is not new. Air separation plants or units (ASUs) take atmospheric air and, through a purification process of cleaning, compressing, and cooling, separate the air into the constituent gases - oxygen, nitrogen, and argon. ASUs are highly computerized, and have very few employees in attendance during operations, which are usually 24 hours a day, 7 days a week. Therefore, process validation, and especially validation of computerized processes, are essential to ensure proper functioning of the process and product quality.

The requirement for computerized process validation has been around since the last major revisions to the current good manufacturing practice regulations which occurred on September 29, 1978. Process validation was addressed in FDA's 1987 Guideline on General Principles of Process Validation. In addition, much has been written about this subject in the industry trade press. Therefore, both the requirement and the agency's expectations have been around for some time.

For yet unvalidated ASUs that have been in operation, i.e., shipping medical grade product, firms may apply, as a remedial measure, retrospective validation. (Product shipped from such unvalidated processes would be adulterated in the CGMP context.) As addressed in the 1987 validation guideline, a key principle in retrospective validation is that current operations are the same as past operations with respect to product specifications, the range of operating conditions, and equipment (ranges and changes). It is important that all changes and controls implemented since the original distribution of medical grade product in the retrospective period have been sufficiently documented. Otherwise, retrospective validation would not be scientifically sound, and older ASUs
would need prospective validation, as would a new ASU that has not distributed medical grade product.

Investigators should refer to Fresh Air 98 for further information on the CGMP requirements for ASUs, focusing on process validation, especially computer systems validation. One other vital CGMP requirement is ensuring that a responsible individual of the ASU firm is the person who releases the finished drug product.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.

What cleaning and process validation do the CGMPs require for production of a bio-batch, where only a single lot has been made?

References: 
21 CFR 211.67, Equipment cleaning and maintenance; 
211.100, Written procedures; deviations; 
Guideline on The Preparation of Investigational New Drug Products, 3/91

The agency has not articulated its expectations regarding process validation or cleaning validation with respect to bio-batches, per se. The closest relevant document is our Guideline on The Preparation of Investigational New Drug Products. In that document we said:

At early clinical stages, where a single batch of drug product may be produced, and where significant formulation and processing changes may make batch replication difficult or inexact, only limited process validation may be possible. In such cases, limited validation, especially for such critical processes as sterilization, should be derived, to the extent possible, from product and process analogs. In addition, data obtained from extensive in-process controls and intensive product testing may be used to demonstrate that the instant run yielded a finished product meeting all of its specifications and quality characteristics. It is expected that more comprehensive process validation will be conducted as additional uniform batches are made under replicated conditions.

You may apply these principles to the bio-batch process and cleaning validation. We would expect adequate cleaning to have been performed and documented and that in-process and end product testing would show instant lots to meet specifications.

Contact for further information: John Dietrick, HFD-325, 301-594-0098; e-mail: dietrickj@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.

In the performance of system suitability, do all replicate standard injections have to be completed before any analyte sample injections are made?

References: 
USP 23 <621> Chromatography: - System Suitability; 
21 CFR 211.160(b), General requirements, Subpart I, Laboratory Controls

Standard practice in the pharmaceutical industry, regarding this subject, is the performance of five replicate injections for an RSD (relative standard deviation) of 2.0%, or six replicate injections for an RSD of 3%, prior to any analyte sample injections.  The referenced USP chapter states: "...To ascertain the effectiveness of the final operating system, it should be subjected to a suitability test prior to use and during testing ...." This indicates that the replicate standard injections should be made, and all system suitability test parameters determined prior to analyte sample injection.

This alternative procedure for standard injections in the performance of system suitability tests may provide a benefit to analysts doing assays which have long run times or sample solutions with short "shelf lives." However, the maxim "caveat emptor" is applicable to this alternative procedure as "let the user beware," in that the time spent on sample analysis may be wasted, and the sample results may be worthless, because they should not be used if the system suitability requirements with respect to RSD are not met.

Contact for further information: Monica E. Caphart, HFD-325, 301-594-0098; e-mail: caphartm@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.

Are tablet press RPMs important enough to be a factor in process  validation?

References: 
See 21 CFR 211.110 (Sampling and testing of in-process materials and drug products), and 
211.100 (Written procedures; deviations).

Yes. Tablet press speed, expressed as revolutions per minute (RPM), is indeed an important factor that needs to be controlled and addressed in tableting validation. Granulation flow characteristics will limit how fast the tableting may proceed; too fast a rate may not permit enough granulation to fall into the dies, resulting in sub-potency. Furthermore, tablet hardness is a function of compression dwell time -- too fast an RPM could mean that the granulation does not experience sufficient compression, and conversely too slow an RPM could mean excessive compression.

Contact for Further Info: Charles Ahn, HFD-325, 301-594-0098, e-mail: ahnc@fdacd.bitnet.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 3) September, 1995.

Policy Questions on Cleaning Validation:  What is the level of detergent residue that would be acceptable  to FDA? What is the basis for arriving at this level, if any?

Reference: 
21 CFR Sec. 211.67, Equipment cleaning and maintenance; and,  
Guide to Inspections of Validation of Cleaning Processes, July 1993 (reformatted May 1994). 

FDA has repeatedly stated that it is the firm's responsibility to establish acceptance limits and be prepared to provide the basis for those limits to FDA. Thus, there is no fixed standard for levels of detergent residue. Any residues must not adversely alter drug product safety, efficacy, quality, or stability.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 2) June, 1995.

Policy Questions on Cleaning Validation:  If the ability of a procedure to clean a piece of equipment made of a particular material, such as 316 stainless steel, is shown to be acceptable and validated, can that "material" specific cleaning procedure be used without "extensive" validation for other pieces of equipment and compounds?

Reference: 
21 CFR Sec. 211.67, Equipment cleaning and maintenance; and,  
Guide to Inspections of Validation of Cleaning Processes, July 1993 (reformatted May 1994). 

No. The design of the equipment is a major component of its cleanability. Therefore, firms should have data that relate to a given piece of equipment.